title: Structure of the cadherin-related neuronal receptor/protocadherin-alpha first extracellular cadherin domain reveals diversity across cadherin families.
abstract: The recent explosion in genome sequencing has revealed the great diversity of the cadherin superfamily. Within the superfamily, protocadherins, which are expressed mainly in the nervous system, constitute the largest subgroup. Nevertheless, the structures of only the classical cadherins are known. Thus, to broaden our understanding of the adhesion repertoire of the cadherin superfamily, we determined the structure of the N-terminal first extracellular cadherin domain of the cadherin-related neuronal receptor/protocadherin-alpha4. The hydrophobic pocket essential for homophilic adhesiveness in the classical cadherins was not found, and the functional significance of this structural domain was supported by exchanging the first extracellular cadherin domains of protocadherin and classical cadherin. Moreover, potentially crucial variations were observed mainly in the loop regions. These included the protocadherin-specific disulfide-bonded Cys-X(5)-Cys motif, which showed Ca(2+)-induced chemical shifts, and the RGD motif, which has been suggested to be involved in heterophilic cell adhesion via the active form of beta1 integrin. Our findings reveal that the adhesion repertoire of the cadherin superfamily is far more divergent than would be predicted by studying the classical cadherins alone.
authors.affiliation: KOKORO Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Morishita
authors.forename: Masataka
authors.initials: M
authors.lastname: Umitsu
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.forename: Naoki
authors.initials: N
authors.lastname: Shibata
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Akutsu
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yagi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Ikegami
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002448:Cell Adhesion; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010802:Phylogeny; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D015820:Cadherins; D002118:Calcium