Structure of the C-terminal laminin G-like domain pair of the laminin alpha2 chain harbouring binding sites for alpha-dystroglycan and heparin.
The laminins are large heterotrimeric glycoproteins with fundamental roles in basement membrane architecture and function. The C-terminus of the laminin alpha chain contains a tandem of five laminin G-like (LG) domains. We report the 2.0 A crystal structure of the laminin alpha2 LG4-LG5 domain pair, which harbours binding sites for heparin and the cell surface receptor alpha-dystroglycan, and is 41% identical to the laminin alpha1 E3 fragment. LG4 and LG5 are arranged in a V-shaped fashion related by a 110 degrees rotation about an axis passing near the domain termini. An extended N-terminal segment is disulfide bonded to LG5 and stabilizes the domain pair. Two calcium ions, one each in LG4 and LG5, are located 65 A apart at the tips of the domains opposite the polypeptide termini. An extensive basic surface region between the calcium sites is proposed to bind alpha-dystroglycan and heparin. The LG4-LG5 structure was used to construct a model of the laminin LG1-LG5 tandem and interpret missense mutations underlying protein S deficiency.
Tisi
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Abteilung Proteinchemie, Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany.
Talts
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JF
Timpl
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Hohenester
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D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000737:chemistry; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000378:metabolism; D049030:Dystroglycans; D006493:Heparin / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011487:Protein Conformation; D018455:Protein S Deficiency / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D007797:Laminin; D008024:Ligands; D008562:Membrane Glycoproteins; C102645:laminin alpha 2; D049030:Dystroglycans; D006493:Heparin; D002118:Calcium