title: Degradation of an old human protein: age-dependent cleavage of γS-crystallin generates a peptide that binds to cell membranes.
abstract: Long-lived proteins exist in a number of tissues in the human body; however, little is known about the reactions involved in their degradation over time. Lens proteins, which do not turn over, provide a useful system to examine such processes. Using a combination of Western blotting and proteomic methodology, age-related changes to a major protein, γS-crystallin, were studied. By teenage years, insoluble intact γS-crystallin was detected, indicative of protein denaturation. This was not the only change, however, because blots revealed evidence of significant cross-linking as well as cleavage of γS-crystallin in all adult lenses. Cleavage at a serine residue near the C terminus was a major reaction that caused the release of a 12-residue peptide, SPAVQSFRRIVE, which bound tightly to lens cell membranes. Several other crystallin-derived peptides with double basic residues also lodged in the cell membrane fraction. Model studies showed that once cleaved from γS-crystallin, SPAVQSFRRIVE adopts a markedly different shape from that in the intact protein. Further, the acquired helical conformation may explain why the peptide seems to affect water permeability. This observation may help explain the changes to cell membranes known to be associated with aging in human lenses. Age-related cleavage of long-lived proteins may therefore yield peptides with untoward biological activity.
authors.affiliation: Save Sight Institute, Macquarie Street, Sydney, New South Wales 2001, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Friedrich
authors.forename: Jackson
authors.initials: J
authors.lastname: Lam
authors.forename: Roger J W
authors.initials: RJ
authors.lastname: Truscott
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D038222:gamma-Crystallins / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D010455:Peptides; D038222:gamma-Crystallins; C077648:CRYGS protein, human