Modulation of integrin activation by an entropic spring in the {beta}-knee.
We show that the length of a loop in the β-knee, between the first and second cysteines (C1-C2) in integrin EGF-like (I-EGF) domain 2, modulates integrin activation. Three independent sets of mutants, including swaps among different integrin β-subunits, show that C1-C2 loop lengths of 12 and longer favor the low affinity state and masking of ligand-induced binding site (LIBS) epitopes. Shortening length from 12 to 4 residues progressively increases ligand binding and LIBS epitope exposure. Compared with length, the loop sequence had a smaller effect, which was ascribable to stabilizing loop conformation, and not interactions with the α-subunit. The data together with structural calculations support the concept that the C1-C2 loop is an entropic spring and an emerging theme that disordered regions can regulate allostery. Diversity in the length of this loop may have evolved among integrin β-subunits to adjust the equilibrium between the bent and extended conformations at different set points.
Smagghe
Benoit J
BJ
From the Immune Disease Institute, Children's Hospital Boston, and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
Huang
Po-Ssu
PS
Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195.
Ban
Yih-En Andrew
YA
Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195.
Baker
David
D
Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195.
Springer
Timothy A
TA
From the Immune Disease Institute, Children's Hospital Boston, and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: springer@idi.harvard.edu.
D004815:Epidermal Growth Factor; D006801:Humans; D039641:Integrin beta Chains / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D039641:Integrin beta Chains; D004815:Epidermal Growth Factor