title: Crystal structure of the actin-binding domain of alpha-actinin 1: evaluating two competing actin-binding models.
abstract: Alpha-actinin belongs to the spectrin family of actin crosslinking and bundling proteins that function as key regulators of cell motility, morphology and adhesion. The actin-binding domain (ABD) of these proteins consists of two consecutive calponin homology (CH) domains. Electron microscopy studies on ABDs appear to support two competing actin-binding models, extended and compact, whereas the crystal structures typically display a compact conformation. We have determined the 1.7A resolution structure of the ABD of alpha-actinin 1, a ubiquitously expressed isoform. The structure displays the classical compact conformation. We evaluated the two binding models by surface conservation analysis. The results show a conserved surface that spans both domains and corresponds to two previously identified actin-binding sites (ABS2 and ABS3). A third, and probably less important site, ABS1, is mostly buried in the compact conformation. However, a thorough examination of existing structures suggests a weak and semi-polar binding interface between the two CHs, leaving open the possibility of domain reorientation or opening. Our results are consistent with a two-step binding mechanism in which the ABD interacts first in the compact form observed in the structures, and then transitions toward a higher affinity state, possibly through minor rearrangement of the domains.
authors.affiliation: Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Borrego-Diaz
authors.forename: Frederic
authors.initials: F
authors.lastname: Kerff
authors.forename: Sung Haeng
authors.initials: SH
authors.lastname: Lee
authors.forename: François
authors.initials: F
authors.lastname: Ferron
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Roberto
authors.initials: R
authors.lastname: Dominguez
mesh_terms: D000185:Actinin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D000199:Actins; D000185:Actinin