Insights into the oligomerization of CRMPs: crystal structure of human collapsin response mediator protein 5.
Collapsin response mediator protein-5 (CRMP-5) is the latest identified member of the CRMP cytosolic phosphoprotein family, which is crucial for neuronal development and repair. CRMPs exist as homo- and/or hetero-tetramers in vivo and participate in signaling transduction, cytoskeleton rearrangements, and endocytosis. CRMP-5 antagonizes many of the other CRMPs' functions either by directly interacting with them or by competing for their binding partners. We determined the crystal structures of a full length and a truncated version of human CRMP-5, both of which form a homo-tetramer similar to those observed in CRMP-1 and CRMP-2. However, solution studies indicate that CRMP-5 and CRMP-1 form weaker homo-tetramers compared with CRMP-2, and that divalent cations, Ca(2+) and Mg(2+), destabilize oligomers of CRMP-5 and CRMP-1, but promote CRMP-2 oligomerization. On the basis of comparative analysis of the CRMP-5 crystal structure, we identified residues that are crucial for determining the preference for hetero-oligomer or homo-oligomer formation. We also show that in spite of being the CRMP family member most closely related to dihydropyrimidinase, CRMP-5 does not have any detectable amidohydrolase activity. The presented findings provide new detailed insights into the structure, oligomerization, and regulation of CRMPs.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Rajesh
R
Ponnusamy
Bernhard
B
Lohkamp
D002118:Calcium / Q000737:chemistry; D020134:Catalytic Domain; D002413:Cations, Divalent; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D006801:Humans; D006867:Hydrolases; D008274:Magnesium / Q000737:chemistry; D008869:Microtubule-Associated Proteins; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011487:Protein Conformation; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry
D002413:Cations, Divalent; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C415087:DPYSL5 protein, human; D006867:Hydrolases; D008274:Magnesium; D002118:Calcium