title: A structural basis for loop C-sheet polymerization in serpins.
abstract: In this study, we report the X-ray crystal structure of an N-terminally truncated variant of the bacterial serpin, tengpin (tengpinDelta42). Our data reveal that tengpinDelta42 adopts a variation of the latent conformation in which the reactive center loop is hyperinserted into the A beta-sheet and removed from the vicinity of the C-sheet. This conformational change leaves the C beta-sheet completely exposed and permits antiparallel edge-strand interactions between the exposed portion of the reactive center loop of one molecule and strand s2C of the C beta-sheet of the neighboring molecule in the crystal lattice. Our structural data thus reveal that tengpinDelta42 forms a loop C-sheet polymer in the crystal lattice. In vivo serpins have a propensity to misfold and form long-chain polymers, a process that underlies serpinopathies such as emphysema, thrombosis and dementia. Native serpins are thought to polymerize via a loop A-sheet mechanism. However, studies on plasminogen activator inhibitor 1 and the S49P variant of human neuroserpin reveal that the latent form of these molecules can also polymerize. Polymerization of latent neuroserpin may be important for the development of familial encephalopathy with neuroserpin inclusion bodies. Our structural data provide a possible mechanism for polymerization by latent serpins.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC 3800, Australia.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ruby H P
authors.initials: RH
authors.lastname: Law
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Buckle
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D017353:Gene Deletion; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D015843:Serpins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D046968:Thermoanaerobacter / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D015843:Serpins