X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding.
Vertebrate collagenases, members of the matrix metalloproteinase (MMP) family, initiate interstitial fibrillar collagen breakdown. It is essential in many biological processes, and unbalanced collagenolysis is associated with diseases such as arthritis, cancer, atherosclerosis, aneurysm, and fibrosis. These metalloproteinases are secreted from the cell as inactive precursors, procollagenases (proMMPs). To gain insights into the structural basis of their activation mechanisms and collagen binding, we have crystallized recombinant human proMMP-1 and determined its structure to 2.2 A resolution. The catalytic metalloproteinase domain and the C-terminal hemopexin (Hpx) domain show the classical MMP-fold, but the structure has revealed new features in surface loops and domain interaction. The prodomain is formed by a three-helix bundle and gives insight into the stepwise activation mechanism of proMMP-1. The prodomain interacts with the Hpx domain, which affects the position of the Hpx domain relative to the catalytic domain. This interaction results in a "closed" configuration of proMMP-1 in contrast to the "open" configuration observed previously for the structure of active MMP-1. This is the first evidence of mobility of the Hpx domain in relation to the catalytic domain, providing an important clue toward the understanding of the collagenase-collagen interaction and subsequent collagenolysis.
Jozic
Daniela
D
Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Bourenkov
Gleb
G
Lim
Ngee-Han
NH
Visse
Robert
R
Nagase
Hideaki
H
Bode
Wolfram
W
Maskos
Klaus
K
D000595:Amino Acid Sequence; D001665:Binding Sites; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004792:Enzyme Precursors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D020781:Matrix Metalloproteinase 1; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary
D004792:Enzyme Precursors; D003094:Collagen; D017364:Collagenases; C022440:procollagenase; D020781:Matrix Metalloproteinase 1