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跟著城市嚮導「老臺北胃」，用味道認識臺北

很多朋友來臺北，
都會問我同一個問題：
「臺北小吃那麼多，到底該從哪裡開始吃？」
夜市裡攤位一字排開、老店藏在巷弄轉角，
看起來都很有名，卻又怕吃錯、踩雷，
結果行程走完，反而沒真正記住臺北的味道。
我常被朋友笑說是「老臺北胃」。
不是因為特別會吃，而是因為在這座城市待久了，
知道哪些味道是陪著臺北人成長的日常。
這篇文章，就是我整理的一份清單。
如果你第一次來臺北，
我會帶你從這 10 樣最具代表性的臺北小吃開始，
不追一時爆紅、不走浮誇路線，
而是讓你吃完後能真正理解
原來，這就是臺灣的小吃文化。
跟著老臺北胃走，
用最簡單的方式，
把臺北的味道，一樣一樣記在心裡。

我怎麼選出這 10 大臺北小吃？

在臺北，
你隨便走進一條夜市或老街，
都可以輕易列出 30 種以上的小吃。
所以這份清單，
不是「臺北最好吃」的排名，
 而是我站在「第一次來臺北的旅客」角度，
做的推薦。
身為一個被朋友稱作「老臺北胃」的人，
我選這 10 樣小吃時，心裡一直放著幾個原則。

一吃就知道：這就是臺灣味

燒烤、火鍋很好吃，
但換個城市、換個國家，也吃得到。
我挑的，是那種
只要一入口，就會讓人聯想到的臺灣味。
 不需要解釋太多，舌頭就能懂。

不只是好吃，而是有「臺北日常感」

臺北的小吃迷人，
不只在味道，
而在它融入生活的方式。
我在意的是：

1. 會不會出現在早餐、宵夜、下班後
   
2. 有沒有陪伴這座城市很久的記憶
   

吃完之後，你會記得臺北

最後一個標準很簡單。
如果你回到家，
還會突然想起某個味道、某碗熱湯、某個攤位的香氣
那它就值得被放進這份清單裡。

接下來的 10 樣臺北小吃，
就是我會親自帶朋友去吃的在地美食。
不趕行程、不拚數量，
而是一口一口，
慢慢認識臺北。

第 1 家：饌堂－黑金滷肉飯（雙連店）｜一碗就懂臺灣人的日常

如果只能用一道料理，
 來解釋臺灣人的日常飲食，
 那我一定會先帶你吃滷肉飯。
在臺北，滷肉飯不是什麼特別的節慶料理，
 而是從早餐、午餐到宵夜，
 默默陪著很多人長大的味道。
而在眾多滷肉飯之中，
饌堂－黑金滷肉飯（雙連店），
 我很常帶第一次來臺北的朋友造訪的一家。

為什麼第一站，我會選饌堂？
饌堂的滷肉飯，走的是**「黑金系」路線**。
滷汁顏色深、香氣厚，
卻不死鹹、不油膩。
滷肉切得細緻，
肥肉入口即化，搭配熱騰騰的白飯，
每一口都是很完整、很臺灣的味道。
對第一次吃滷肉飯的旅客來說，
這種風味夠經典、也夠穩定，
不需要太多心理準備，就能理解為什麼臺灣人這麼愛它。

不只是好吃，而是「現在的臺北感」
饌堂並不是那種躲在深巷裡的老攤，
空間乾淨、節奏俐落，
卻沒有失去滷肉飯該有的靈魂。
這也是我會推薦給旅客的原因之一：
它保留了臺灣小吃的核心味道，
同時也讓第一次來臺北的人，
吃得安心、坐得舒服。

老臺北胃的帶路小提醒
如果是第一次來：

1. 一定要點招牌黑金滷肉飯
   
2. 可以加一顆滷蛋，風味會更完整
   
3. 搭配簡單的小菜，就很有臺灣家常感
   

這不是那種吃完會驚呼「哇！」的料理，
而是會讓你在幾口之後，
慢慢理解
原來，臺灣人的日常，就是這樣被一碗飯照顧著。

地址：103臺北市大同區雙連街55號1樓

電話：0225501379

菜單：https://bio.site/ZhuanTang

第 2 家：富宏牛肉麵｜臺北深夜也醒著的一碗熱湯

如果說滷肉飯代表的是臺灣人的日常，
 那牛肉麵，
 就是很多臺北人心中最有份量的一餐。
而在臺北提到牛肉麵，
 富宏牛肉麵，
 幾乎是夜貓族、加班族、外地旅客一定會被帶去的一站。

為什麼老臺北胃會帶你來吃富宏？
富宏最讓人印象深刻的，
不是華麗裝潢，
而是那鍋永遠冒著熱氣的紅燒湯頭。
湯色濃而不混，
帶著牛骨與醬香慢慢熬出的厚度，
喝起來溫潤、不刺激，
卻會在嘴裡留下很深的記憶點。
牛肉給得大方，
燉到軟嫩卻不鬆散，
搭配彈性十足的麵條，
每一口都很直接、很臺北。

不分時間，任何時候都適合的一碗麵
富宏牛肉麵最迷人的地方，
在於它陪伴了無數個臺北的夜晚。
不管是深夜下班、看完演唱會、
或是剛抵達臺北、還沒適應時差，
這裡總有一碗熱湯在等你。
對旅客來說，
這種不用算時間、不用擔心打烊的安心感，
本身就是一種臺北特色。

老臺北胃的帶路小提醒
第一次來富宏，我會這樣點：

1. 紅燒牛肉麵是首選
   
2. 如果想吃得更過癮，可以加點牛筋或牛肚
   
3. 湯先喝一口原味，再視情況調整辣度
   

這不是精緻料理，
卻是一碗能在任何時刻撐住你的牛肉麵。
在臺北，
很多夜晚，
就是靠這樣一碗熱湯走過來的。

地址：108臺北市萬華區洛陽街67號

電話：0223713028

菜單：https://www.facebook.com/pages/富宏牛肉麵-原建宏牛肉麵/

第 3 家：士林夜市・吉彖皮蛋涼麵｜臺北夏天最有記憶點的一口清爽

如果你在夏天來到臺北，
 一定會很快發現一件事
 這座城市，真的很熱。
也正因為這樣，
 臺北的小吃世界裡，
 才會出現像「涼麵」這樣的存在。
而在士林夜市，
 吉彖皮蛋涼麵，
 就是我很常帶旅客來吃的一家。

為什麼在夜市，我會帶你吃涼麵？
很多人對夜市的印象，
都是炸物、熱湯、重口味。
但真正的臺北夜市，
其實也很懂得照顧人的胃。
吉彖的涼麵，
冰涼的麵條拌上濃郁芝麻醬，
再加上切得細緻的皮蛋，
入口的第一瞬間，
就是一種「被降溫」的感覺。
那種清爽，
不是沒味道，
而是在濃香與清涼之間取得剛剛好的平衡。

皮蛋，是靈魂，也是臺灣味的關鍵
對很多外國旅客來說，
皮蛋是既好奇、又有點猶豫的存在。
但我常說，
如果要嘗試皮蛋，
涼麵是一個非常溫柔的起點。
芝麻醬的香氣會先接住味蕾，
皮蛋的風味則在後段慢慢出現，
不衝、不嗆，
反而多了一層深度。
很多人吃完後，
都會露出那種「原來是這樣啊」的表情。

老臺北胃的帶路小提醒
第一次點吉彖皮蛋涼麵，我會建議：

1. 一定要選皮蛋款，才吃得到特色
   
2. 醬料先拌勻，再吃，風味會更完整
   
3. 如果天氣真的很熱，這一碗會救你一整晚
   

這不是華麗的小吃，
卻非常臺北。
在悶熱的夜晚，
站在夜市人潮裡，
吃著一碗涼麵，
你會突然明白——

原來臺北的小吃，連氣候都一起考慮進去了。

地址：111臺北市士林區基河路114號

電話：0981014155

菜單：https://www.facebook.com/profile.php?id=100064238763064

第 4 家：胖老闆誠意肉粥｜臺北人深夜最踏實的一碗粥

如果你問我，
 臺北人在深夜、下班後，
 最容易感到被安慰的食物是什麼——
 我會毫不猶豫地說：肉粥。
而提到肉粥，
 胖老闆誠意肉粥，
 就是很多老臺北人口中的那一味。

為什麼這一碗粥，會被叫做「誠意」？
胖老闆的肉粥，看起來很簡單。
白粥、肉燥、配菜，
沒有華麗擺盤，也沒有複雜作法。
但真正坐下來吃，你會發現：
這碗粥，不敷衍任何一個細節。
粥體滑順、不稀薄，
肉燥香而不膩，
搭配各式家常小菜，
一口一口吃下去，
很自然就會放慢速度。
這種味道，
不是要你驚艷，
而是要你安心。

這不是觀光小吃，而是臺北人的生活片段
胖老闆誠意肉粥，
最迷人的地方，
就是它的客人。
你會看到：

1. 剛下班的上班族
   
2. 熬夜後來吃一碗熱粥的人
   
3. 熟門熟路、點菜不用看菜單的老客人
   

這些畫面，
比任何裝潢都更能說明這家店在臺北的位置。
對旅客來說，
這是一個走進臺北人日常的入口。

老臺北胃的帶路小提醒
第一次來吃，我會這樣建議：

1. 肉粥一定要點，這是主角
   
2. 配幾樣小菜一起吃，才有完整體驗
   
3. 不用急，慢慢吃，這碗粥就是要你放鬆
   

這不是為了拍照而存在的小吃，
而是那種
**會讓人記得「那天晚上，我在臺北吃了一碗很溫暖的粥」**的味道。

地址：10491臺北市中山區長春路89-3號

電話：0913806139

菜單：https://lin.ee/xxbYZyS

第 5 家：圓環邊蚵仔煎｜夜市裡最不能缺席的臺灣經典

如果要選一道
 最常出現在旅客記憶裡的臺灣小吃，
 蚵仔煎一定排得上前幾名。
而在臺北，
 圓環邊蚵仔煎，
 就是那種很多臺北人從小吃到大的存在。

為什麼蚵仔煎，這麼能代表臺灣？
蚵仔煎的魅力，
不在於精緻，
而在於它把幾種看似簡單的食材，
煎成了一種獨特的口感。
新鮮蚵仔的海味、
雞蛋的香氣、
地瓜粉形成的滑嫩外皮，
最後再淋上甜中帶鹹的醬汁，
一口下去，
就是夜市的完整畫面。
這種味道，
很難在其他國家找到替代品。

圓環邊，吃的是記憶感
圓環邊蚵仔煎，
沒有多餘的包裝，
也不刻意迎合潮流。
它留下來的原因很簡單
味道夠穩、節奏夠快、
讓人一吃就知道「對，就是這個」。
對旅客來說，
這是一家
不需要研究、不需要比較，就能安心點蚵仔煎的地方。

老臺北胃的帶路小提醒
第一次吃蚵仔煎，我會這樣建議：

1. 趁熱吃，口感最好
   
2. 不用急著加辣，先吃原味
   
3. 醬汁是靈魂，別急著把它拌掉
   

蚵仔煎不是細嚼慢嚥的料理，
它屬於人聲鼎沸、鍋鏟作響的夜市時刻。
站在人群裡，
吃著一盤熱騰騰的蚵仔煎，
你會很清楚地感受到
這，就是臺北的夜晚。

地址：103臺北市大同區寧夏路46號

電話：0225580198

菜單：https://oystera.com.tw/menu

第 6 家：阿淑清蒸肉圓｜第一次吃肉圓，就該從這裡開始

說到臺灣小吃，
 很多人腦中一定會出現「肉圓」兩個字。
但真正吃過之後才會發現，
 肉圓，從來不只有一種樣子。
在臺北，
 阿淑清蒸肉圓，
 就是我很常拿來介紹「清蒸派肉圓」的一家。

清蒸肉圓，和你想像的不一樣
不少旅客對肉圓的第一印象，
來自油炸版本，
外皮厚、口感重。
而阿淑的清蒸肉圓，
完全是另一個方向。
外皮晶瑩、滑嫩，
帶著自然的彈性，
不油、不膩，
一入口反而顯得清爽。
內餡扎實，
豬肉香氣清楚，
搭配特製醬汁，
味道層次簡單卻很乾淨。

為什麼我會推薦給第一次來臺北的旅客？
因為這顆肉圓，
不需要適應期。
它不刺激、不厚重，
即使是第一次嘗試臺灣小吃的人，
也能輕鬆接受。
對旅客來說，
這是一顆
「吃得懂、也記得住」的肉圓。

老臺北胃的帶路小提醒
第一次來阿淑，我會這樣吃：

1. 直接點一顆清蒸肉圓，吃原味
   
2. 醬汁先別全部拌開，邊吃邊調整
   
3. 放慢速度，感受外皮的口感變化
   

這不是夜市裡熱鬧喧囂的料理，
而是那種
安靜地展現臺灣小吃功夫的味道。
當你吃完這顆肉圓，
會更明白一件事
臺灣小吃的魅力，
往往藏在這些細節裡。

地址：242新北市新莊區復興路一段141號

電話：0229975505

第 7 家：胡記米粉湯｜一碗最貼近臺北早晨的味道

如果說前面幾樣小吃，
 是臺北的熱鬧與記憶，
 那麼米粉湯，
 就是這座城市最真實的日常。
而在臺北，
 胡記米粉湯，
 是很多人從小吃到大的存在。

為什麼米粉湯，這麼「臺北」？
米粉湯不是重口味料理，
它靠的不是刺激，
而是一碗清澈卻有深度的湯。
胡記的湯頭，
用豬骨慢慢熬出香氣，
喝起來清爽、不油，
卻能在喉嚨留下溫度。
米粉細軟，
吸附湯汁後入口順滑，
簡單到不能再簡單，
卻正是臺北人習以為常的早晨風景。

配菜，才是這一碗的靈魂延伸
在胡記吃米粉湯，
主角雖然是湯，
但真正讓人滿足的，
往往是那些小菜。
紅燒肉、豬內臟、燙青菜，
隨意點上幾樣，
湯一口、菜一口，
就是很多臺北人記憶中的早餐組合。
對旅客來說，
這是一種
不需要解釋，就能融入的臺北生活感。

老臺北胃的帶路小提醒
第一次來胡記，我會這樣建議：

1. 一定要點米粉湯，湯先喝
   
2. 再配 1～2 樣小菜，體驗會完整很多
   
3. 這一餐適合慢慢吃，不用趕
   

這不是為了觀光而存在的小吃，
而是一碗
每天準時出現在臺北人生活裡的湯。
當你坐在店裡，
聽著湯勺碰撞的聲音，
你會突然感覺到——
原來，臺北的早晨，
就是從這樣一碗米粉湯開始的。

地址：106臺北市大安區大安路一段9號1樓

電話：0227212120

第 8 家：藍家割包｜一口咬下的臺灣街頭記憶

如果要選一道
 外國旅客一看到就會好奇、吃完又會記住的小吃，
 割包，一定在名單裡。
而在臺北，
 藍家割包，
 就是我很放心帶旅客來認識這道經典的一站。

割包，為什麼被叫做「臺灣漢堡」？
割包的結構其實很簡單：
鬆軟的白饅頭、
燉得入味的滷五花肉、
酸菜、花生粉、香菜。
但真正迷人的，
是這些元素組合在一起時，
形成的層次感。
肉香、甜味、鹹味、清爽度，
在一口之間同時出現，
沒有誰搶戲，
卻彼此剛好。
這種平衡感，
正是臺灣小吃很迷人的地方。

藍家割包不是走浮誇路線，
它給人的感覺很直接
就是你期待中的割包樣子。
饅頭柔軟不乾，
五花肉肥瘦比例恰到好處，
入口即化卻不膩口，
花生粉的甜香收尾，
讓整體味道非常完整。
對第一次吃割包的旅客來說，
這是一個
不會出錯、也很容易愛上的版本。

老臺北胃的帶路小提醒
第一次吃藍家割包，我會這樣建議：

1. 直接點招牌割包，不要改配料
   
2. 如果有香菜，建議保留，味道會更完整
   
3. 趁熱吃，饅頭口感最好
   

割包不是精緻料理，
卻非常有記憶點。
站在街頭，
拿著一顆熱騰騰的割包，
邊走邊吃，
你會很清楚地感受到
這一口，就是臺灣的街頭生活。

地址：100臺北市中正區羅斯福路三段316巷8弄3號

電話：0223682060

菜單：https://instagram.com/lan_jia_gua_bao?utm_medium=copy_link

第 9 家：御品元冰火湯圓｜臺北夜晚最溫柔的一碗甜

吃了一整天的臺北小吃，
 到了這個時候，
 胃其實已經差不多滿了。
但只要天氣一涼，
 或夜色慢慢降下來，
 你還是會想找一碗——
 不是為了吃飽，而是為了舒服的甜點。
這時候，我通常會帶你來 御品元冰火湯圓。

為什麼叫「冰火」？這碗湯圓的關鍵就在這裡
御品元最有特色的地方，
就在於它的「冰火交錯」。
熱騰騰的湯圓，
外皮軟糯、內餡濃香，
搭配冰涼清甜的桂花蜜湯，
一口下去，
溫度在嘴裡交替出現。
不是衝突，
而是一種很細膩的平衡。
這樣的吃法，
也正是臺灣甜點很擅長的地方——
不張揚，但很有記憶點。

這是一碗，會讓人慢下來的甜點
和夜市裡熱鬧的甜品不同，
御品元的冰火湯圓，
更像是一個讓人停下腳步的存在。
你會發現，
坐在這裡吃湯圓的人，
說話聲都會不自覺地變小。
對旅客來說，
這不只是吃甜點，
而是一個
把白天的熱鬧慢慢收進回憶裡的時刻。

老臺北胃的帶路小提醒
第一次吃御品元，我會這樣建議：

1. 點招牌冰火湯圓，體驗完整特色
   
2. 先單吃湯圓，再搭配湯一起吃
   
3. 放慢速度，這一碗不適合趕時間
   

這不是為了拍照而存在的甜點，
而是一碗
會讓你記得「那天晚上在臺北，很舒服」的湯圓。

地址：106臺北市大安區通化街39巷50弄31號

電話：0955861816

菜單：https://instagram.com/lan_jia_gua_bao

第 10 家：頃刻間綠豆沙牛奶專賣店｜把臺北的味道，留在最後一口清甜

走到這一站，
 其實已經不需要再吃什麼大份量的東西了。
這時候，
 最適合的，
 是一杯不吵鬧、不張揚，
 卻會默默留在記憶裡的飲品。
頃刻間綠豆沙牛奶，
 就是我很常用來替一天畫下句點的選擇。

綠豆沙牛奶，為什麼這麼「臺灣」？
在臺灣，
飲料不只是解渴，
而是一種生活節奏。
綠豆沙牛奶看起來簡單，
但真正好喝的版本，
靠的是火候、比例，
還有耐心。
頃刻間的綠豆沙，
口感細緻、不粗顆，
甜度自然、不膩口，
牛奶的加入，
讓整杯變得柔順而溫和。
這不是衝擊味蕾的飲料，
而是一種
喝完之後，會覺得剛剛那一刻很舒服的甜。

為什麼我會用它當作最後一站？
因為它很臺北。
你可以外帶，
邊走邊喝；
也可以站在店門口，
慢慢把杯子喝空。
沒有儀式感，
卻很真實。
對旅客來說，
這杯綠豆沙牛奶，
就像是把今天吃過的所有味道，
溫柔地整理好，
帶走。

老臺北胃的帶路小提醒
第一次喝頃刻間，我會這樣建議：

1. 直接點招牌綠豆沙牛奶
   
2. 正常甜就很剛好，不用特別調整
   
3. 找個角落慢慢喝，別急著趕路
   

這一杯，
不會讓你驚呼，
卻會在回程的路上，
突然想起來。
原來，臺北的味道，是這樣結束一天的。

地址：111臺北市士林區小北街1號

電話：0228818619

菜單：https://instagram.com/chill_out_moment?igshid=YmMyMTA2M2Y=

如果只有 3 天的自助旅行在臺北，怎麼吃這 10 家？

第一次來臺北，
時間有限、胃容量也有限，
與其每一家都趕，不如照著節奏吃。
這份 3 天小吃路線，
是老臺北胃會帶朋友實際走的版本：
不爆走、不硬塞，
讓你每天都吃得剛剛好。

臺北 3 天小吃推薦行程表（老臺北胃版本）

雖然每個小吃的地點都有一點距離，但是你也知道，好吃的小吃，是值得你花一點時間前往品嘗
老臺北胃的小提醒

1. 不需要每一家都點到最滿
   
2. 留一點餘裕，才會想再回來
   
3. 臺北小吃的魅力，不在於吃多少，而在於記住了什麼味道
   

當你照著這 3 天走完，
你會發現，
臺北不是靠一兩道名菜被記住的，
而是靠這些看似日常、卻很真實的小吃。
下次再來，老臺北胃再帶你吃更深的那一輪。

老臺北胃帶路｜這 10 口，就是我心中的臺北

寫到這裡，
 其實已經不是在推薦哪一家小吃了。
而是在回頭看，
 這座城市，是怎麼用食物陪著人生活的。
滷肉飯、牛肉麵、肉粥、米粉湯，
 不是為了成為觀光名單而存在，
 而是每天默默出現在臺北人的日子裡。
夜市裡的蚵仔煎、涼麵、割包，
 熱鬧、吵雜、節奏很快，
 卻也正是臺北最真實的樣子。
而最後那碗湯圓、那杯綠豆沙牛奶，
 則是在一天結束時，
 替味蕾留下一個溫柔的句點。

如果你問我，
「這 10 家是不是臺北最好吃的小吃？」
我會說，
它們不一定是排行榜第一名，
卻是我真的會帶朋友去吃的版本。
因為它們吃得到：

1. 臺北人的日常
   
2. 巷弄裡的熟悉感
   
3. 不需要解釋，就能被理解的味道
   

如果你是第一次來臺北，
跟著這份清單走，
你不一定會吃得最飽，
但你一定會記得——
臺北，是什麼味道。
而如果有一天，
你又再回到這座城市，
走進熟悉的街口、
看到冒著熱氣的小攤，
你也會開始懂得，
為什麼老臺北胃，
總是記得這些看似平凡的滋味。
因為，真正留在心裡的，
從來不是吃過多少，
而是哪一口，讓你想起臺北。

圓環邊蚵仔煎會不會膩？

走完這 10 家，

你可能會發現一件事圓環邊蚵仔煎會不會太甜？

臺北的小吃，其實不急著被你記住。

它們就安靜地存在在街角、夜市、轉彎處，圓環邊蚵仔煎價格合理嗎？

等你有一天，再回到這座城市。圓環邊蚵仔煎真的推薦嗎？

如果你是第一次來臺北，御品元冰火湯圓吃過會回訪嗎？

希望這份「老臺北胃帶路」的清單，

能幫你少一點猶豫、多一點安心。

不用擔心踩雷，阿淑清蒸肉圓好吃嗎？

也不用為了排行而奔波，胖老闆誠意肉粥好吃嗎？

只要照著節奏走，

你就會吃到屬於自己的臺北味道。

而如果你已經來過臺北，

那更希望這篇文章，圓環邊蚵仔煎本地人會吃嗎？

能帶你走進那些

你可能錯過、卻一直都在的日常小吃。

因為真正迷人的旅行，

從來不是把清單全部打勾，

而是某一天，

你突然想起那碗飯、那口湯、那杯甜，頃刻間綠豆沙牛奶專賣店會踩雷嗎？

然後在心裡對自己說一句：富宏牛肉麵真的好吃嗎？

「下次再去臺北，還想再吃一次。」

把這篇文章存起來、分享給一起旅行的人，

或是在規劃行程時，再回來看看。

讓味道，成為你認識臺北的方式。

下一次來臺北，

別急著走遠。

老臺北胃，富宏牛肉麵女生會喜歡嗎？

會一直在這些地方，

等你再回來。

Adhesion G protein-coupled receptors have a large extracellular region (shown in green and orange) that extends into space outside the cell. Credit: Eric Smith Researchers at the University of Chicago have successfully captured detailed images of adhesion G protein-coupled receptors, along with an alternative method for activating them. This breakthrough paves the way for innovative drug design opportunities. Nearly 35% of drugs approved by the Food and Drug Administration (FDA) target G protein-coupled receptors (GPCRs), a group of proteins embedded in cell membranes that enable cells to communicate. Among these, adhesion G protein-coupled receptors (aGPCRs) form the second-largest family in humans. As their name implies, aGPCRs facilitate cell adhesion, or the ability of cells to stick together, while transmitting signals within the body. aGPCRs play crucial roles in processes like tissue growth, immune system function, and organ development. However, disruptions in their function can lead to serious conditions such as cancer, neurological disorders, and growth abnormalities. Despite their significance, no drugs have been approved to target aGPCRs. This is largely because these receptors are exceptionally large, complex, and challenging to study. New research from the University of Chicago combines two powerful imaging techniques to study the complete structure of a common aGPCR, including how its long and complex extracellular region interacts with the transmembrane region embedded in the cell surface. The different positions and movements of the extracellular region appear to be an important way to activate the receptor. “This opens up new opportunities for drugging adhesion GPCRs, because now we are showing that the extracellular region is communicating with the transmembrane region,” said Demet Araç, PhD, Associate Professor of Biochemistry and Molecular Biology at UChicago and senior author of the new study. The results were published this month in Nature Communications. Capturing new images and new configurations The extracellular region of an aGPCR extends from the cell membrane into space outside the cell, where it can bind to molecules and receptors from other cells. It consists of several domains, including the GPCR Autoproteolysis INducing (GAIN) domain, which can cleave itself into two pieces. The common understanding of how to activate an aGPCR is that a ligand from outside the cell attaches to one of the extracellular domains and exerts a force that separates the GAIN domain from its other piece, a peptide called the tethered agonist (TA) that remains attached to the transmembrane region. When the TA is separated, it can move and interact with the transmembrane region to initiate signaling, but a growing body of biochemistry research shows that many aGPCR functions don’t rely on this cleavage-dependent mechanism. Separating the GAIN domain is also irreversible, leaving the receptor in a constant “on” state, which may be harmful for the cell. Sometimes a cell may need to toggle a receptor on and off, so there must be some other way of doing it. Araç’s lab has been working for 11 years to reveal the structure of full-length aGPCRs, hoping to learn how incoming signals are transmitted from outside to inside the cell. These receptors are notoriously difficult to fully understand because the extracellular regions have many complex and distinct configurations. Graduate student Szymon Kordon, PhD, led the new study, picking up the work of a previous student to capture images of the complete structure of Latrophilin3, an aGPCR involved in developing brain synapses that have also been linked to attention deficit hyperactivity disorder and several cancers. Kordon and Araç optimized generation and purification of Latrophilin3 and captured initial electron microscopy images, but they faced numerous challenges to get a good picture of the receptor. They then worked with Antony Kossiakoff, PhD, the Otho S.A. Sprague Distinguished Service Professor of Biochemistry and Molecular Biology at UChicago, to create a synthetic antibody that could attach to the aGPCR. This antibody stabilized the extracellular region and lent it a distinctive shape that allowed Kordon to capture the full receptor structure using cryo-electron microscopy (cryo-EM), an imaging technique that freezes cells and molecules for a snapshot. The resulting images became the first known structure of a complete aGPCR. The cryo-EM images showed that the GAIN domain of the receptor assumed several different positions in relation to the cell surface. Each different position of the GAIN domain created a different contact point between it and the transmembrane region. The researchers wondered if these different configurations could be a different means of communicating to the cell, without separating the GAIN domain completely. So, they partnered with Reza Vafabakhsh, PhD, Associate Professor of Molecular Biosciences at Northwestern University, and Kristina Cechova, PhD, a postdoctoral researcher at Northwestern, to run a second series of experiments that tracked the movements of the extracellular regions. Cechova and the team used Förster resonance energy transfer (FRET) imaging, which can measure the energy transfer between molecules that are close to each other. After attaching fluorescent markers to different points on both the extracellular and transmembrane regions of the aGPCR, they could track its movements as it responded to adhesion forces pulling and pushing on it. What they saw confirmed their suspicion about the function of the different configurations. “Different conformational states correlated to different signaling activity of the receptor,” Kordon said. “That shows the functional relevance of these conformations on the downstream signaling in the cell.” Kordon, who graduated in 2024, later received the Best Dissertation Award from the Department of Biochemistry and Molecular Biology at UChicago for his work on this project. A new way of activating receptors Araç said that now that they have a better understanding of the structure of aGPCRs and how they work, they can see the potential for targeting them with drugs in the same way as other receptors. Researchers could engineer antibodies like the ones used in this study to stabilize them for imaging but designed to manipulate their activity instead. Since aGPCRs have distinct shapes and structures, these antibodies could be very precise as well. With 33 different aGPCRs already identified in humans, there are plenty of opportunities. “This could be the future of drugging adhesion GPCRs,” Araç said. “The advantage of this is that extracellular regions are very different from each other, so you can target them with a drug that doesn’t bind to other receptors and cause unwanted side effects.” Reference: “Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function” by Szymon P. Kordon, Kristina Cechova, Sumit J. Bandekar, Katherine Leon, Przemysław Dutka, Gracie Siffer, Anthony A. Kossiakoff, Reza Vafabakhsh and Demet Araç, 4 December 2024, Nature Communications. DOI: 10.1038/s41467-024-54836-4 The study was supported by the National Institutes of Health, the Chicago Biomedical Consortium, and the National Cancer Institute. Additional authors include Sumit J. Bandekar, Katherine Leon, and Przemysław Dutka from UChicago and Gracie Siffer from Northwestern.

A study conducted by researchers at the University of Rhode Island has demonstrated evidence that evolutionary changes within species can drive ecological modifications. By observing changes in the leg length of anole lizards in the Bahamas and their subsequent impact on vegetation growth and spider populations, the study suggests that changes in an organism’s traits through evolution can affect predator-prey relationships and other ecological interactions, essentially creating a feedback loop where evolution influences environmental change. While it’s well-established that environmental factors shape the evolution of species, a recent study illustrates a reciprocal relationship where the evolutionary adaptations of species, in turn, impact their environment. The narrative of the peppered moths is a well-known example of evolution in action. During the Industrial Revolution in England, the pollution from coal smoke darkened the tree bark around the urban areas, rendering the white-bodied peppered moths highly visible to predators, which led to a rapid decline in their population. Simultaneously, the previously uncommon black-bodied moths flourished, becoming the dominant variety due to their ability to blend into the newly darkened environment. This phenomenon is often cited as a classic illustration of how environmental alterations can drive the evolution of species. However, in recent times, researchers have started to explore the inverse scenario. Could it be possible that there is a reciprocal relationship where the evolution of a species influences and instigates changes in its ecosystem? Now, a new study by researchers at the University of Rhode Island shows some of the best evidence yet for that very phenomenon. In research published in the Proceedings of the National Academy of Sciences, the researchers show that an evolutionary change in the length of lizards’ legs can have a significant impact on vegetation growth and spider populations on small islands in the Bahamas. This is one of the first times, the researchers say, that such dramatic evolution-to-environment effects have been documented in a natural setting. Male brown anole lizard. Credit: Oriol Lapiedra Investigating the Evolution-Environment Feedback Loop “The idea here is that, in addition to the environment shaping the traits of organisms through evolution, those trait changes should feed back and drive changes in predator-prey relationships and other ecological interactions between species,” said Jason Kolbe, a professor of biological sciences at the University of Rhode Island and one of the study’s senior authors. “And we really need to understand how those dynamics work so we can make predictions about how populations are going to persist, and what sort of ecological changes might result.” For the last 20 years, Kolbe and his colleagues have been observing the evolutionary dynamics of anole lizard populations on a chain of tiny islands in the Bahamas. The chain is made up of around 40 islands ranging from a few dozen to a few hundred meters in the area—small enough that the researchers can keep close tabs on the lizards living there. And the islands are far enough apart that lizards can’t easily hop from one island to another, so distinct populations can be isolated from each other. Previous research had shown that brown anoles adapt quickly to the characteristics of the surrounding vegetation. In habitats where the diameter of the brush and tree limbs is smaller, natural selection favors lizards with shorter legs, which enable individuals to move more quickly when escaping predators or chasing a snack. In contrast, lankier lizards tend to fare better where the tree and plant limbs are thicker. Researchers have shown that this limb-length trait can evolve quickly in brown anoles—in just a few generations. A new study by researchers at the University of Rhode Island shows some of the best evidence yet for a feedback loop phenomenon in which species evolution drives ecological change. Credit: Kolbe Labs/University of Rhode Island For this new study, Kolbe and his team wanted to see how this evolved limb-length trait might affect the ecosystems on the tiny Bahamian islands. The idea was to separate short- and long-legged lizards on islands of their own, then look for differences in how the lizard populations affect the ecology of their island homes. Armed with specialized lizard wrangling gear—poles with tiny lassos made of dental floss at the end—the team captured hundreds of brown anoles. They then measured the leg length of each lizard, keeping the ones whose limbs were either especially long or especially short and returning the rest to the wild. Once they had distinct populations of short- and long-limbed lizards, they set each population free on islands that previously had no lizards living on them. Since the experimental islands were mostly covered by smaller diameter vegetation, the researchers expected that the short-legged lizards would be better adapted to that environment, that is, more maneuverable and better able to catch prey in the trees and brush. The question the researchers wanted to answer was whether the ecological effects of those highly effective hunters could be detected. After eight months, the researchers checked back on the islands to look for ecological differences between islands stocked with the short- and long-legged groups. The differences, it turned out, were substantial. On islands with shorter-legged lizards, populations of web spiders—a key prey item for brown anoles—were reduced by 41% compared to islands with lanky lizards. There were significant differences in plant growth as well. Because the short-legged lizards were better at preying on insect herbivores, plants flourished. On islands with short-legged lizards, buttonwood trees had twice as much shoot growth compared to trees on islands with long-legged lizards, the researchers found. The results, Kolbe says, help to bring the interaction between ecology and evolution full circle. Closing the Loop Between Evolution and Ecology “These findings help us to close that feedback loop,” Kolbe said. “We knew from previous research that ecological factors shape limb length, and now we show the reciprocal relationship of that evolutionary change on the environment.” Understanding the full scope of interactions between evolution and ecology will be helpful in predicting environments’ outcomes, the researchers say—particularly as human activities accelerate the pace of both evolutionary and ecological change worldwide. Reference: “Experimentally simulating the evolution-to-ecology connection: Divergent predator morphologies alter natural food webs” by Jason J. Kolbe, Sean T. Giery, Oriol Lapiedra, Kelsey P. Lyberger, Jessica N. Pita-Aquino, Haley A. Moniz, Manuel Leal, David A. Spiller, Jonathan B. Losos, Thomas W. Schoener and Jonah Piovia-Scott, 5 June 2023, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2221691120 The study was funded by the National Science Foundation.

Rhinolophus rouxi, which inhabits parts of South Asia, was identified as a likely but undetected betacoronavirus host by the study authors. Credit: Brock and Sherri Fenton Researchers have developed predictive models to identify bats that may harbor betacoronaviruses. Their study uses machine learning to dynamically update wildlife virus sampling, emphasizing bat conservation to prevent outbreaks. Daniel Becker, an assistant professor of biology in the University of Oklahoma’s Dodge Family College of Arts and Sciences, has been leading a proactive modeling study over the last year and a half to identify bat species that are likely to carry betacoronaviruses, including but not limited to SARS-like viruses. The study “Optimizing predictive models to prioritize viral discovery in zoonotic reservoirs,” which was published by Lancet Microbe, was guided by Becker; Greg Albery, a postdoctoral fellow at Georgetown University’s Bansal Lab; and Colin J. Carlson, an assistant research professor at Georgetown’s Center for Global Health Science and Security. It also included collaborators from the University of Idaho, Louisiana State University, University of California Berkeley, Colorado State University, Pacific Lutheran University, Icahn School of Medicine at Mount Sinai, University of Glasgow, Université de Montréal, University of Toronto, Ghent University, University College Dublin, Cary Institute of Ecosystem Studies, and the American Museum of Natural History. The Verena Consortium’s Role in Viral Forecasting Becker and colleagues’ study is part of the broader efforts of an international research team called the Verena Consortium (viralemergence.org), which works to predict which viruses could infect humans, which animals host them, and where they could emerge. Albery and Carlson were co-founders of the consortium in 2020, with Becker as a founding member. Despite global investments in disease surveillance, it remains difficult to identify and monitor wildlife reservoirs of viruses that could someday infect humans. Statistical models are increasingly being used to prioritize which wildlife species to sample in the field, but the predictions being generated from any one model can be highly uncertain. Scientists also rarely track the success or failure of their predictions after they make them, making it hard to learn and make better models in the future. Together, these limitations mean that there is high uncertainty in which models may be best suited to the task. Methodology of Bat Host Prediction In this study, researchers used bat hosts of betacoronaviruses, a large group of viruses that includes those responsible for SARS and COVID-19, as a case study for how to dynamically use data to compare and validate these predictive models of likely reservoir hosts. The study is the first to prove that machine learning models can optimize wildlife sampling for undiscovered viruses and illustrates how these models are best implemented through a dynamic process of prediction, data collection, validation and updating. In the first quarter of 2020, researchers trained eight different statistical models that predicted which kinds of animals could host betacoronaviruses. Over more than a year, the team then tracked discovery of 40 new bat hosts of betacoronaviruses to validate initial predictions and dynamically update their models. The researchers found that models harnessing data on bat ecology and evolution performed extremely well at predicting new hosts of betacoronaviruses. In contrast, cutting-edge models from network science that used high-level mathematics – but less biological data – performed roughly as well or worse than expected at random. Findings and Implications for Bat Conservation Importantly, their revised models predicted over 400 bat species globally that could be undetected hosts of betacoronaviruses, including not only in southeast Asia but also in sub-Saharan Africa and the Western Hemisphere. Although 21 species of horseshoe bats (in the Rhinolophus genus) are known to be hosts of SARS-like viruses, researchers found at least two-fourths of plausible betacoronavirus reservoirs in this bat genus might still be undetected. “One of the most important things our study gives us is a data-driven shortlist of which bat species should be studied further,” said Becker, who adds that his team is now working with field biologists and museums to put their predictions to use. “After identifying these likely hosts, the next step is then to invest in monitoring to understand where and when betacoronaviruses are likely to spill over.” Becker added that although the origins of SARS-CoV-2 remain uncertain, the spillover of other viruses from bats has been triggered by forms of habitat disturbance, such as agriculture or urbanization. “Bats conservation is therefore an important part of public health, and our study shows that learning more about the ecology of these animals can help us better predict future spillover events,” he said. For more on this research, see Shall We Play a Game? Researchers Use AI To Search for the Next COVID/SARS-Like Virus. Reference: “Optimising predictive models to prioritise viral discovery in zoonotic reservoirs” by Daniel J Becker, PhD; Gregory F Albery, PhD; Anna R Sjodin, PhD; Timothée Poisot, PhD; Laura M Bergner, PhD; Binqi Chen; Lily E Cohen, MPhil; Tad A Dallas, PhD; Evan A Eskew, PhD; Anna C Fagre, DVM; Maxwell J Farrell, PhD; Sarah Guth, BA; Barbara A Han, PhD; Nancy B Simmons, PhD; Michiel Stock, PhD; Emma C Teeling, PhD and Colin J Carlson, PhD, 10 January 2022, The Lancet Microbe. DOI: 10.1016/S2666-5247(21)00245-7

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