A family of 16-kDa pancreatic secretory stress proteins form highly organized fibrillar structures upon tryptic activation

A group of 16-kDa proteins, synthesized and secreted by rat pancreatic acin ar cells and composed of pancreatic stone protein (PSP/reg) and isoforms of pancreatitis-associated protein (PAP), show structural homologies, includi ng conserved amino acid sequences, cysteine residues, and highly sensitive N-terminal trypsin cleavage sites, as well as conserved functional response s in conditions of pancreatic stress. Trypsin activation of recombinant str ess proteins or counterparts contained in rat pancreatic juice (PSP/reg, PA P I and PAP III) resulted in conversion of 16-kDa soluble proteins into 14- kDa soluble isoforms (pancreatic thread protein and pancreatitis-associated thread protein, respectively) that rapidly polymerize into insoluble sedim enting structures, Activated thread proteins show long lived resistance to a wide spectrum of proteases contained in pancreatic juice, including serin e proteases and metalloproteinases, In contrast, PAP II, following activati on with trypsin or pancreatic juice, does not form insoluble structures and is rapidly digested by pancreatic proteases, Scanning and transmission ele ctron microscopy indicate that activated thread proteins polymerize into hi ghly organized fibrillar structures with helical configurations. Through bu ndling, branching, and extension processes, these fibrillar structures form dense matrices that span large topological surfaces. These findings sugges t that PSP/reg and PAP I and III isoforms consist of a family of highly reg ulated soluble secretory stress proteins, which, upon trypsin activation, c onvert into a family of insoluble helical thread proteins. Dense extracellu lar matrices, composed of helical thread proteins organized into higher ord ered matrix structures, may serve physiological functions within luminal co mpartments in the exocrine pancreas.