title: An unusual allosteric mobility of the C-terminal helix of a high-affinity alphaL integrin I domain variant bound to ICAM-5.
abstract: Integrins are cell surface receptors that transduce signals bidirectionally across the plasma membrane. The key event of integrin signaling is the allosteric regulation between its ligand-binding site and the C-terminal helix (alpha7) of integrin's inserted (I) domain. A significant axial movement of the alpha7 helix is associated with the open, active conformation of integrins. We describe the crystal structure of an engineered high-affinity I domain from the integrin alpha(L)beta(2) (LFA-1) alpha subunit in complex with the N-terminal two domains of ICAM-5, an adhesion molecule expressed in telencephalic neurons. The finding that the alpha7 helix swings out and inserts into a neighboring I domain in an upside-down orientation in the crystals implies an intrinsically unusual mobility of this helix. This remarkable feature allows the alpha7 helix to trigger integrin's large-scale conformational changes with little energy penalty. It serves as a mechanistic example of how a weakly bound adhesion molecule works in signaling.
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Zhang
authors.forename: Jose M
authors.initials: JM
authors.lastname: Casasnovas
authors.forename: Moonsoo
authors.initials: M
authors.lastname: Jin
authors.forename: Jin-huan
authors.initials: JH
authors.lastname: Liu
authors.forename: Carl G
authors.initials: CG
authors.lastname: Gahmberg
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
authors.forename: Jia-huai
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D040881:CD11a Antigen / Q000737:chemistry* / Q000378:metabolism*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D040881:CD11a Antigen; D015815:Cell Adhesion Molecules; D050505:Mutant Proteins