Surface loops of trypsin-like serine proteases as determinants of function.
Trypsin and chymotrypsin-like serine proteases from family S1 (clan PA) constitute the largest protease group in humans and more generally in vertebrates. The prototypes chymotrypsin, trypsin and elastase represent simple digestive proteases in the gut, where they cleave nearly any protein. Multidomain trypsin-like proteases are key players in the tightly controlled blood coagulation and complement systems, as well as related proteases that are secreted from diverse immune cells. Some serine proteases are expressed in nearly all tissues and fluids of the human body, such as the human kallikreins and kallikrein-related peptidases with specialization for often unique substrates and accurate timing of activity. HtrA and membrane-anchored serine proteases fulfill important physiological tasks with emerging roles in cancer. The high diversity of all family members, which share the tandem β-barrel architecture of the chymotrypsin-fold in the catalytic domain, is conferred by the large differences of eight surface loops, surrounding the active site. The length of these loops alters with insertions and deletions, resulting in remarkably different three-dimensional arrangements. In addition, metal binding sites for Na+, Ca2+ and Zn2+ serve as regulatory elements, as do N-glycosylation sites. Depending on the individual tasks of the protease, the surface loops determine substrate specificity, control the turnover and allow regulation of activation, activity and degradation by other proteins, which are often serine proteases themselves. Most intriguingly, in some serine proteases, the surface loops interact as allosteric network, partially tuned by protein co-factors. Knowledge of these subtle and complicated molecular motions may allow nowadays for new and specific pharmaceutical or medical approaches.
['Goettig|Peter|P|', 'Brandstetter|Hans|H|', 'Magdolen|Viktor|V|']
D000818:Animals D001665:Binding Sites D020134:Catalytic Domain D006801:Humans D008958:Models, Molecular D000072757:Protein Conformation, beta-Strand D012697:Serine Endopeptidases D013329:Structure-Activity Relationship D013379:Substrate Specificity
Surface loops Allosteric network Chymotrypsin fold Regulatory mechanism Structure-function relationship Zymogenicity