1KFX

Crystal Structure of Human m-Calpain Form I

Summary for 1KFX

• Entry DOI: 10.2210/pdb1kfx/pdb
• Related: 1KFU
• Descriptor: M-CALPAIN LARGE SUBUNIT, M-CALPAIN SMALL SUBUNIT (3 entities in total)
• Functional Keywords: regulation, papain-like, thiol-protease, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P17655; Cytoplasm (By similarity): P04632
• Total number of polymer chains: 2
• Total formula weight: 101231.88

Authors

Strobl, S.,Fernandez-Catalan, C.,Braun, M.,Huber, R.,Masumoto, H.,Nakagawa, K.,Irie, A.,Sorimachi, H.,Bourenkow, G.,Bartunik, H.,Suzuki, K.,Bode, W. (deposition date: 2001-11-23, release date: 2001-12-07, Last modification date: 2023-08-16)

Primary citation

Strobl, S.,Fernandez-Catalan, C.,Braun, M.,Huber, R.,Masumoto, H.,Nakagawa, K.,Irie, A.,Sorimachi, H.,Bourenkow, G.,Bartunik, H.,Suzuki, K.,Bode, W.
The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium.
Proc.Natl.Acad.Sci.USA, 97:588-592, 2000

PubMed Abstract: Calpains (calcium-dependent cytoplasmic cysteine proteinases) are implicated in processes such as cytoskeleton remodeling and signal transduction. The 2.3-A crystal structure of full-length heterodimeric [80-kDa (dI-dIV) + 30-kDa (dV+dVI)] human m-calpain crystallized in the absence of calcium reveals an oval disc-like shape, with the papain-like catalytic domain dII and the two calmodulin-like domains dIV+dVI occupying opposite poles, and the tumor necrosis factor alpha-like beta-sandwich domain dIII and the N-terminal segments dI+dV located between. Compared with papain, the two subdomains dIIa+dIIb of the catalytic unit are rotated against one another by 50 degrees, disrupting the active site and the substrate binding site, explaining the inactivity of calpains in the absence of calcium. Calcium binding to an extremely negatively charged loop of domain dIII (an electrostatic switch) could release the adjacent barrel-like subdomain dIIb to move toward the helical subdomain dIIa, allowing formation of a functional catalytic center. This switch loop could also mediate membrane binding, thereby explaining calpains' strongly reduced calcium requirements in vivo. The activity status at the catalytic center might be further modulated by calcium binding to the calmodulin domains via the N-terminal linkers.

PubMed: 10639123
DOI: 10.1073/pnas.97.2.588

Experimental method

X-RAY DIFFRACTION (3.15 Å)