title: The dimer interface of the membrane type 1 matrix metalloproteinase hemopexin domain: crystal structure and biological functions.
abstract: Homodimerization is an essential step for membrane type 1 matrix metalloproteinase (MT1-MMP) to activate proMMP-2 and to degrade collagen on the cell surface. To uncover the molecular basis of the hemopexin (Hpx) domain-driven dimerization of MT1-MMP, a crystal structure of the Hpx domain was solved at 1.7 Å resolution. Two interactions were identified as potential biological dimer interfaces in the crystal structure, and mutagenesis studies revealed that the biological dimer possesses a symmetrical interaction where blades II and III of molecule A interact with blades III and II of molecule B. The mutations of amino acids involved in the interaction weakened the dimer interaction of Hpx domains in solution, and incorporation of these mutations into the full-length enzyme significantly inhibited dimer-dependent functions on the cell surface, including proMMP-2 activation, collagen degradation, and invasion into the three-dimensional collagen matrix, whereas dimer-independent functions, including gelatin film degradation and two-dimensional cell migration, were not affected. These results shed light on the structural basis of MT1-MMP dimerization that is crucial to promote cellular invasion.
authors.affiliation: Arbeitsgruppe Proteinaseforschung, Max-Planck-Institut fuer Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Tochowicz
authors.forename: Peter
authors.initials: P
authors.lastname: Goettig
authors.forename: Richard
authors.initials: R
authors.lastname: Evans
authors.forename: Robert
authors.initials: R
authors.lastname: Visse
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shitomi
authors.forename: Ralf
authors.initials: R
authors.lastname: Palmisano
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.forename: Daniel
authors.initials: D
authors.lastname: Franke
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svergun
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Wolfram
authors.initials: W
authors.lastname: Bode
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003461:Crystallography; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology*; D006367:HeLa Cells; D006466:Hemopexin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008565:Membrane Proteins; D006466:Hemopexin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14