title: Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions.
abstract: ADAMs (a disintegrin and metalloproteases) are members of the metzincin superfamily of metalloproteases. Among integrins binding to disintegrin domains of ADAMs are alpha(9)beta(1) and alpha(v)beta(3), and they bind in an RGD-independent and an RGD-dependent manner, respectively. Human ADAM15 is the only ADAM with the RGD motif in the disintegrin domain. Thus, both integrin alpha(9)beta(1) and alpha(v)beta(3) recognize the ADAM15 disintegrin domain. We determined how these integrins recognize the ADAM15 disintegrin domain by mutational analysis. We found that the Arg(481) and the Asp-Leu-Pro-Glu-Phe residues (residues 488-492) were critical for alpha(9)beta(1) binding, but the RGD motif (residues 484-486) was not. In contrast, the RGD motif was critical for alpha(v)beta(3) binding, but the other residues flanking the RGD motif were not. As the RX(6)DLPEF alpha(9)beta(1) recognition motif (residues 481-492) is conserved among ADAMs, except for ADAM10 and 17, we hypothesized that alpha(9)beta(1) may recognize disintegrin domains in all ADAMs except ADAM10 and 17. Indeed we found that alpha(9)beta(1) bound avidly to the disintegrin domains of ADAM1, 2, 3, and 9 but not to the disintegrin domains of ADAM10 and 17. As several ADAMs have been implicated in sperm-oocyte interaction, we tested whether the functional classification of ADAMs, based on specificity for integrin alpha(9)beta(1), applies to sperm-egg binding. We found that the ADAM2 and 15 disintegrin domains bound to oocytes, but the ADAM17 disintegrin domain did not. Furthermore, the ADAM2 and 15 disintegrin domains effectively blocked binding of sperm to oocytes, but the ADAM17 disintegrin domain did not. These results suggest that oocytes and alpha(9)beta(1) have similar binding specificities for ADAMs and that alpha(9)beta(1), or a receptor with similar specificity, may be involved in sperm-egg interaction during fertilization. As alpha(9)beta(1) is a receptor for many ADAM disintegrins and alpha(9)beta(1) and ADAMs are widely expressed, alpha(9)beta(1)-ADAM interaction may be of a broad biological importance.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Clotilde
authors.initials: C
authors.lastname: Huet
authors.forename: Takehiko
authors.initials: T
authors.lastname: Tarui
authors.forename: Sergey
authors.initials: S
authors.lastname: Kupriyanov
authors.forename: Hai-Zhen
authors.initials: HZ
authors.lastname: Liu
authors.forename: Wilma
authors.initials: W
authors.lastname: Puzon-McLaughlin
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Zhang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Eva
authors.initials: E
authors.lastname: Engvall
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
mesh_terms: D051722:ADAM Proteins; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000378:metabolism; D016466:CHO Cells; D017124:Conserved Sequence; D006224:Cricetinae; D019483:Disintegrins / Q000378:metabolism*; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008565:Membrane Proteins / Q000145:classification / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000145:classification / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013084:Sperm-Ovum Interactions / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D019483:Disintegrins; D016023:Integrins; D008565:Membrane Proteins; D019030:Receptors, Vitronectin; C113256:integrin alpha 9 beta 1; D001120:Arginine; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C490902:Adam15 protein, mouse; D008666:Metalloendopeptidases