title: Fluorescence correlation spectroscopic study of serpin depolymerization by computationally designed peptides.
abstract: Members of the serine proteinase inhibitor (serpin) family play important roles in the inflammatory and coagulation cascades. Interaction of a serpin with its target proteinase induces a large conformational change, resulting in insertion of its reactive center loop (RCL) into the main body of the protein as a new strand within beta-sheet A. Intermolecular insertion of the RCL of one serpin molecule into the beta-sheet A of another leads to polymerization, a widespread phenomenon associated with a general class of diseases known as serpinopathies. Small peptides are known to modulate the polymerization process by binding within beta-sheet A. Here, we use fluorescence correlation spectroscopy (FCS) to probe the mechanism of peptide modulation of alpha(1)-antitrypsin (alpha(1)-AT) polymerization and depolymerization, and employ a statistical computationally-assisted design strategy (SCADS) to identify new tetrapeptides that modulate polymerization. Our results demonstrate that peptide-induced depolymerization takes place via a heterogeneous, multi-step process that begins with internal fragmentation of the polymer chain. One of the designed tetrapeptides is the most potent antitrypsin depolymerizer yet found.
authors: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Pramit
authors: P
authors: Chowdhury
authors: Wei
authors: W
authors: Wang
authors: Stacey
authors: S
authors: Lavender
authors: Michelle R
authors: MR
authors: Bunagan
authors: Jason W
authors: JW
authors: Klemke
authors: Jia
authors: J
authors: Tang
authors: Jeffrey G
authors: JG
authors: Saven
authors: Barry S
authors: BS
authors: Cooperman
authors: Feng
authors: F
authors: Gai
mesh_terms: D000595:Amino Acid Sequence; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D015843:Serpins / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism
chemical_list: D010455:Peptides; D015843:Serpins; D000515:alpha 1-Antitrypsin