Structural basis of the adaptive molecular recognition by MMP9.
Matrix metalloproteinase (MMPs) are critical for the degradation of extracellular matrix components and, therefore, need to be regulated tightly. Almost all MMPs share a homologous C-terminal haemopexin-like domain (PEX). Besides its role in macromolecular substrate processing, the PEX domains appear to play a major role in regulating MMP activation, localisation and inhibition. One intriguing property of MMP9 is its competence to bind different proteins, involved in these regulatory processes, with high affinity at an overlapping recognition site on its PEX domain. With the crystal structure of the PEX9 dimer, we present the first example of how PEX domains accomplish these diverse roles. Blade IV of PEX9 mediates the non-covalent and predominantly hydrophobic dimerisation contact. Large shifts of blade III and, in particular, blade IV, accompany the dimerisation, resulting in a remarkably asymmetric homodimeric structure. The asymmetry provides a novel mechanism of adaptive protein recognition, where different proteins (PEX9, PEX1, and TIMP1) can bind with high affinity to PEX9 at an overlapping site. Finally, the structure illustrates how the dimerisation generates new properties on both a physico-chemical and functional level.
Cha
Hyunju
H
Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, D-82152, Martinsried, Germany.
Kopetzki
Erhard
E
Huber
Robert
R
Lanzendörfer
Martin
M
Brandstetter
Hans
H
D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D002118:Calcium; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents; D019281:Dimerization; D006466:Hemopexin / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D008670:Metals; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012964:Sodium / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate; D013431:Sulfates / Q000737:chemistry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000737:chemistry
D003432:Cross-Linking Reagents; D007477:Ions; D008670:Metals; D013431:Sulfates; D019715:Tissue Inhibitor of Metalloproteinase-1; D001224:Aspartic Acid; D012967:Sodium Dodecyl Sulfate; D006466:Hemopexin; D012964:Sodium; D020780:Matrix Metalloproteinase 9; D002118:Calcium