title: Intrasteric inhibition mediates the interaction of the I/LWEQ module proteins Talin1, Talin2, Hip1, and Hip12 with actin.
abstract: The I/LWEQ module superfamily is a class of actin-binding proteins that contains a conserved C-terminal actin-binding element known as the I/LWEQ module. I/LWEQ module proteins include the metazoan talins, the cellular slime mold talin homologues TalA and TalB, fungal Sla2p, and the metazoan Sla2 homologues Hip1 and Hip12 (Hip1R). These proteins possess a similar modular organization that includes an I/LWEQ module at their C-termini and either a FERM domain or an ENTH domain at their N-termini. As a result of this modular organization, I/LWEQ module proteins may serve as linkers between cellular compartments, such as the plasma membrane and the endocytic machinery, and the actin cytoskeleton. Previous studies have shown that I/LWEQ module proteins bind to F-actin. In this report, we have determined the affinity of the I/LWEQ module proteins Talin1, Talin2, huntingtin interacting protein-1 (Hip1), and the Hip1-related protein (Hip1R/Hip12) for F-actin and identified a conserved structural element that interferes with the actin binding capacity of these proteins. Our data support the hypothesis that the actin-binding determinants in native talin and other I/LWEQ module proteins are cryptic and indicate that the actin binding capacities of Talin1, Talin2, Hip1, and Hip12 are regulated by intrasteric occlusion of primary actin-binding determinants within the I/LWEQ module. We have also found that the I/LWEQ module contains a dimerization motif and stabilizes actin filaments against depolymerization. This activity may contribute to the function of talin in cell adhesion and the roles of Hip1, Hip12 (Hip1R), and Sla2p in endocytosis.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 800 Rose Street, Lexington, Kentucky 40536-0298, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Senetar
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Foster
authors.forename: Richard O
authors.initials: RO
authors.lastname: McCann
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D017124:Conserved Sequence; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D019281:Dimerization; D004705:Endocytosis; D006801:Humans; D007536:Isomerism; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017433:Protein Structure, Secondary; D011817:Rabbits; D016608:Talin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D033921:Vesicular Transport Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; C489537:HIP1R protein, human; C489536:Hip1 protein, mouse; D008840:Microfilament Proteins; D020033:Protein Isoforms; C436513:TLN2 protein, human; D016608:Talin; D033921:Vesicular Transport Proteins