Calpains: enzymes of vision?
Globally, cataract accounts for the majority of cases of treatable blindness and the lens opacification associated with cataract is primarily due to the insolubilisation of crystallins, proteins essential for the transparency of the lens. Recent studies have suggested that a major cause of this insolubilisation may be the unregulated proteolysis of crystallins by calpains. These are intracellular cysteine proteases whose activation requires the presence of Ca2+ and elevated levels of lens Ca2+ is a condition strongly associated with cataract. Calpain 2 appears to be the major calpain involved in animal cataractogenesis and the strongest candidate of the calpains for a role in human cataractogenesis but despite intensive study, the mechanism(s) underlying activation of the enzyme both in cataractogenesis and normal lens function are unclear. Recently, the high-resolution structure of calpain 2 was recently solved and a structural basis for the Ca2+-dependence of the enzyme's activity has been putatively established. Other recent studies have suggested that membrane interaction(s) may play a role in lowering the Ca2+-requirements of calpain 2 activation and most recently, strongly supporting this suggestion, several lipid interactive regions in the enzyme have been identified. Here, we review progress in understanding of the role played by calpain 2 in cataractogenesis and the possible use of inhibitors of the enzyme as anti-cataract agents.
Biswas
Suman
S
Bristol Eye Hospital, Bristol, England, UK.
Harris
Frederick
F
Dennison
Sarah
S
Singh
Jai Paul
JP
Phoenix
David
D
D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002386:Cataract / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D003459:Crystallins / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004789:Enzyme Activation; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D012995:Solubility; D014785:Vision, Ocular / Q000502:physiology*
D003459:Crystallins; D015853:Cysteine Proteinase Inhibitors; D002154:Calpain; D002118:Calcium