title: The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family.
abstract: Zyme/protease M/neurosin/human kallikrein 6 (hK6) is a member of the human kallikrein family of trypsin-like serine proteinases and was originally identified as being down-regulated in metastatic breast and ovarian tumors when compared with corresponding primary tumors. Recent evidence suggests that hK6 may serve as a circulating tumor marker in ovarian cancers. In addition, it was described in the brain of Parkinson's disease and Alzheimer's disease patients, where it is implicated in amyloid precursor protein processing. It is thus a biomarker for these diseases. To examine the mechanism of activation of hK6, we have solved the structure of its proform, the first of a human kallikrein family member. The proenzyme displays a fold that exhibits chimeric features between those of trypsinogen and other family members. It lacks the characteristic "kallikrein loop" and forms the six disulfide bridges of trypsin. Pro-hK6 displays a completely closed specificity pocket and a unique conformation of the regions involved in structural rearrangements upon proteolytic cleavage activation. This points to a novel activation mechanism, which could be extrapolated to other human kallikreins.
authors.affiliation: Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Cientificas, c/Jordi Girona 18-26, Barcelona 08034, Spain. xgrcri@ibmb.csic.es
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
authors.forename: Alex
authors.initials: A
authors.lastname: Bayés
authors.forename: Georgia
authors.initials: G
authors.lastname: Sotiropoulou
authors.forename: Georgios
authors.initials: G
authors.lastname: Pampalakis
authors.forename: Theodoros
authors.initials: T
authors.lastname: Tsetsenis
authors.forename: Virtudes
authors.initials: V
authors.lastname: Villegas
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Avilés
authors.forename: Miquel
authors.initials: M
authors.lastname: Coll
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D004220:Disulfides; D004583:Electrons; D005091:Exons; D006801:Humans; D007610:Kallikreins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D004220:Disulfides; C103551:KLK6 protein, human; D007610:Kallikreins