The conformational states of talin autoinhibition complex and its activation under forces

Yan Zeng,Sheng Ye,Rongguang Zhang,Xianqiang Song,Qinghua Ji,Jizhong Lou,Yong Zhang

doi:10.1007/s11427-015-4873-9

Abstract

Talin is an integrin-binding protein located at focal adhesion site and serves as both an adapter and a force transmitter. Its integrin binding activity is regulated by the intramolecular autoinhibition interaction between its F3 and RS domains. Here, we used atomic force microscopy to measure the strength of talin autoinhibition complex. Our results suggest that the lifetime of talin autoinhibition complex shows weak catch bond behavior and does not change significantly at smaller forces, while it drops rapidly at larger forces (>10 pN). Moreover, besides the complex conformation revealed by crystal structure, our molecular dynamics (MD) simulations indicate the possible existence of another stable conformation. Further analysis indicates that forces may regulate the equilibrium of the two stable binding states and result in the non-exponential force dependence of the binding lifetime. Our findings reveal a negative regulation mechanism on talin activation and provide a new point of view on the function of talin in focal adhesion.

Highlights

Talin is a largely abundant cytosolic protein containing more than 2500 amino acids
To understand the potential effect of force and dynamic process on talin activation, we have investigated the dissociation of talin F2F3 and rod segment 1822 (RS) domain by single-molecule force spectroscopy using atomic force microscopy (AFM) and molecular dynamics (MD) simulations
Our results suggest that talin F2F3/RS autoinhibition complex may interconverts between two stable conformations and the equilibrium can be regulated by applied forces

Summary

Introduction

Talin is a largely abundant cytosolic protein containing more than 2500 amino acids It links integrin and actin filaments, plays important roles in mechanical signaling pathway, and regulates various integrin-mediated cell adhesion events [1]. RIAM functions as scaffold that connects talin with Rap, and the membrane targeting sequences in Rap recruit the complex to the membrane, thereby promoting talin binding to integrin [19] Another talin regulator phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of plasma membrane, can bind with talin and block the interaction of talin F3/RS [5]. As a molecule located at focal adhesion and a linker between integrin and actin filaments, activated talin must adapt the function at the complicated mechanical conditions in vivo

Methods

Results

Conclusion