State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.
Nano Lett. 2020 Sep 9;20(9):6387-6395. doi: 10.1021/acs.nanolett.0c01957. Epub 2020 Aug 10.
Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.
桥连整合蛋白-1（BIN1）是一种香蕉形分子家族，参与细胞膜的管状化。为了理解 BIN1 剪接异构体的曲率敏感性和功能作用，我们在细胞培养基底上设计了垂直纳米棒来产生高曲率和低曲率。当单独表达时，具有磷酸肌醇结合基序的 BIN1 异构体（pBIN1）优先出现在高曲率纳米棒端，与它们在心肌细胞中的膜管状化非常吻合。相比之下，没有磷酸肌醇结合基序的普遍存在的 BIN1 异构体（uBIN1）没有亲和力与纳米棒周围的膜结合，但在心肌细胞中沿 Z 线积累。重要的是，在 pBIN1-uBIN1 共表达中，pBIN1 将 uBIN1 募集到纳米棒端的高曲率膜上，而 uBIN1 将 otherwise messy pBIN1 小管附着到 Z 线上。BIN1 异构体的互补合作（组合 BIN1）代表了心肌细胞中 Z 线沿 T 小管形成的一种新机制。BIN1 剪接的失调，例如在心肌梗死期间，导致 T 小管的紊乱，而纠正 uBIN1/pBIN1 比例可以挽救心脏病中的 T 小管形态。
