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Abstract:
The deepest evolutionary branches of the trypsin/chymotrypsin family of
serine proteases are represented by the digestive enzymes of the
gastrointestinal tract and the multi-domain proteases of the blood
coagulation and complement system. Similar to the very old digestive
system, highly diverse cleavage specificities emerged in various cell
lineages of the immune defense system during vertebrate evolution. The
four neutrophil serine proteases (NSPs) expressed in the myelomonocyte
lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil
serine protease 4, collectively display a broad repertoire of (S1)
specificities. The origin of NSPs can be traced back to a circulating
liver-derived trypsin-like protease, the complement factor D ancestor,
whose activity is tightly controlled by substrate-induced activation and
TNF alpha-induced locally upregulated protein secretion. However, the
present-day descendants are produced and converted to mature enzymes in
precursor cells of the bone marrow and are safely sequestered in
granules of circulating neutrophils. The potential site and duration of
action of these cell-associated serine proteases are tightly controlled
by the recruitment and activation of neutrophils, by stimulus-dependent
regulated secretion of the granules, and by various soluble inhibitors
in plasma, interstitial fluids, and in the inflammatory exudate. An
extraordinary dynamic range and acceleration of immediate defense
responses have been achieved by exploiting the high structural
plasticity of the trypsin fold.
