The Tail of Integrins, Talin, and Kindlins

Abstract

Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.

Integrins as therapeutic targets: lessons and opportunities

“…The talin rod domain can also bind to the talin head-domain in an anti-parallel manner, masking the integrin-binding regions and exerting an auto-inhibitory function. This is an important regulatory mechanism for preventing inappropriate integrin activation 118 .…”

Toward correlating structure and mechanics of platelets

“…This transition is regulated by intracellular events utilizing 2 cytoplasmic proteins, talin and kindlin, in the presence of platelet agonists. 6 Both proteins directly bind the cytoplasmic tail of b-integrin subunits and thereby trigger integrin activation.…”

A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

“…Extensive genetic and cell biological studies have established that talin is crucial for regulating a wide variety of integrin-mediated cell adhesiondependent processes, such as cell-shape change, growth, differentiation, and migration [2][3][4]. Talin is large in size, with 2541 amino acids, and can be divided into two major segments, an N-terminal head (1-433, talin-H, 50 kDa) that contains a FERM (four-point-one-protein/ ezrin/radixin/moesin) domain (86-400, talin-FERM) and a C-terminal rod (482-2541, talin-R, 220 kDa) that contains a series of consecutive helical bundles followed by an actin-binding motif [2][3][4]. Talin-FERM, which engages with heterodimeric (α/β) integrin adhesion receptors, can be further divided into F1, F2, and F3 subdomains, with F3 specifically interacting with integrin β cytoplasmic tails (CTs) [2][3][4].…”

“…Talin is large in size, with 2541 amino acids, and can be divided into two major segments, an N-terminal head (1-433, talin-H, 50 kDa) that contains a FERM (four-point-one-protein/ ezrin/radixin/moesin) domain (86-400, talin-FERM) and a C-terminal rod (482-2541, talin-R, 220 kDa) that contains a series of consecutive helical bundles followed by an actin-binding motif [2][3][4]. Talin-FERM, which engages with heterodimeric (α/β) integrin adhesion receptors, can be further divided into F1, F2, and F3 subdomains, with F3 specifically interacting with integrin β cytoplasmic tails (CTs) [2][3][4]. Because of its capacity to bind both integrin and actin, talin has long been recognized as a mechanical linker between the ECM and actin cytoskeleton to regulate cell adhesion and morphology [5].…”