PMID- 10639123
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 2
DP  - 2000 Jan 18
TI  - The crystal structure of calcium-free human m-calpain suggests an electrostatic
      switch mechanism for activation by calcium.
PG  - 588-92
AB  - 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.
FAU - Strobl, S
AU  - Strobl S
AD  - Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D 82 152
      Planegg-Martinsried, Germany.
FAU - Fernandez-Catalan, C
AU  - Fernandez-Catalan C
FAU - Braun, M
AU  - Braun M
FAU - Huber, R
AU  - Huber R
FAU - Masumoto, H
AU  - Masumoto H
FAU - Nakagawa, K
AU  - Nakagawa K
FAU - Irie, A
AU  - Irie A
FAU - Sorimachi, H
AU  - Sorimachi H
FAU - Bourenkow, G
AU  - Bourenkow G
FAU - Bartunik, H
AU  - Bartunik H
FAU - Suzuki, K
AU  - Suzuki K
FAU - Bode, W
AU  - Bode W
LA  - eng
SI  - PDB/1DKV
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Isoenzymes)
RN  - EC 3.4.22.- (Calpain)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Calcium/chemistry/*physiology
MH  - Calpain/*chemistry/metabolism
MH  - Catalytic Domain
MH  - Computer Graphics
MH  - Crystallography, X-Ray
MH  - Enzyme Activation
MH  - Humans
MH  - Isoenzymes/chemistry
MH  - Molecular Sequence Data
MH  - Protein Conformation
MH  - Rats
MH  - Static Electricity
PMC - PMC15374
EDAT- 2000/01/19 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/01/19 09:00
PHST- 2000/01/19 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/01/19 09:00 [entrez]
AID - 10.1073/pnas.97.2.588 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):588-92. doi: 10.1073/pnas.97.2.588.