Calpains are Ca(2+) dependent intracellular cysteine proteases that cleave a wide range of protein substrates to help implement Ca(2+) signaling in the cell. The major isoforms of this enzyme family, calpain-1 and calpain-2, are heterodimers of a large and a small subunit, with the main dimer interface being formed through their C-terminal penta-EF hand (PEF) domains. Calpain-3, or p94, is a skeletal muscle-specific isoform that is genetically linked to limb-girdle muscular dystrophy. Biophysical and modeling studies with the PEF domain of calpain-3 support the suggestion that full-length calpain-3 exists as a homodimer. Here, we report the crystallization of calpain-3's PEF domain and its crystal structure in the presence of Ca(2+) , which provides evidence for the homodimer architecture of calpain-3 and supports the molecular model that places a protease core at either end of the elongated dimer. Unlike other calpain PEF domain structures, the calpain-3 PEF domain contains a Ca(2+) bound at the EF5-hand used for homodimer association. Three of the four Ca(2+) -binding EF-hands of the PEF domains are concentrated near the protease core, and have the potential to radically change the local charge within the dimer during Ca(2+) signaling. Examination of the homodimer interface shows that there would be steric clashes if the calpain-3 large subunit were to try to pair with a calpain small subunit. Database Structural data are available in the Protein Data Bank database under accession number 4OKH. STRUCTURED DIGITAL ABSTRACT: Calpain-3 and Calpain-3 bind by x-ray crystallography (View interaction).
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Crystal structure of calpain-3 penta-EF-hand (PEF) domain - a homodimerized PEF family member with calcium bound at the fifth EF-hand.,Partha SK, Ravulapalli R, Allingham JS, Campbell RL, Davies PL FEBS J. 2014 Jul;281(14):3138-49. doi: 10.1111/febs.12849. Epub 2014 Jun 9. PMID:24846670<ref>PMID:24846670</ref>
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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== References ==
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Revision as of 06:18, 13 August 2014
Crystal structure of calpain-3 penta-EF-hand domain
[CAN3_HUMAN] Autosomal recessive limb girdle muscular dystrophy type 2A. The disease is caused by mutations affecting the gene represented in this entry.
Calpains are Ca(2+) dependent intracellular cysteine proteases that cleave a wide range of protein substrates to help implement Ca(2+) signaling in the cell. The major isoforms of this enzyme family, calpain-1 and calpain-2, are heterodimers of a large and a small subunit, with the main dimer interface being formed through their C-terminal penta-EF hand (PEF) domains. Calpain-3, or p94, is a skeletal muscle-specific isoform that is genetically linked to limb-girdle muscular dystrophy. Biophysical and modeling studies with the PEF domain of calpain-3 support the suggestion that full-length calpain-3 exists as a homodimer. Here, we report the crystallization of calpain-3's PEF domain and its crystal structure in the presence of Ca(2+) , which provides evidence for the homodimer architecture of calpain-3 and supports the molecular model that places a protease core at either end of the elongated dimer. Unlike other calpain PEF domain structures, the calpain-3 PEF domain contains a Ca(2+) bound at the EF5-hand used for homodimer association. Three of the four Ca(2+) -binding EF-hands of the PEF domains are concentrated near the protease core, and have the potential to radically change the local charge within the dimer during Ca(2+) signaling. Examination of the homodimer interface shows that there would be steric clashes if the calpain-3 large subunit were to try to pair with a calpain small subunit. Database Structural data are available in the Protein Data Bank database under accession number 4OKH. STRUCTURED DIGITAL ABSTRACT: Calpain-3 and Calpain-3 bind by x-ray crystallography (View interaction).
Crystal structure of calpain-3 penta-EF-hand (PEF) domain - a homodimerized PEF family member with calcium bound at the fifth EF-hand.,Partha SK, Ravulapalli R, Allingham JS, Campbell RL, Davies PL FEBS J. 2014 Jul;281(14):3138-49. doi: 10.1111/febs.12849. Epub 2014 Jun 9. PMID:24846670[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Partha SK, Ravulapalli R, Allingham JS, Campbell RL, Davies PL. Crystal structure of calpain-3 penta-EF-hand (PEF) domain - a homodimerized PEF family member with calcium bound at the fifth EF-hand. FEBS J. 2014 Jul;281(14):3138-49. doi: 10.1111/febs.12849. Epub 2014 Jun 9. PMID:24846670 doi:http://dx.doi.org/10.1111/febs.12849
