Colonic amyloidosis, computational analysis of the major amyloidogenic species, Serum Amyloid A
2012 (English)In: Computational biology and chemistry (Print), ISSN 1476-9271, E-ISSN 1476-928X, Vol. 39, 29-34 p.Article in journal (Refereed) Published
Amyloidosis is characterized by misfolding of proteins. The clinical gastrointestinal manifestations of amyloidosis may mimic other disease, such as inflammatory bowel disease or colonic cancer. As these patients have a high risk for bleeding and poor wound healing following surgery it is important to diagnose them correctly and do a careful preoperative assessment. The most common form of colonic amyloidosis is caused by Serum Amyloid A (SAA), an acute phase protein of unknown function. It is expressed in response to inflammation and the increased levels may lead to amyloidosis. The main treatment is to suppress the acute phase response and thereby reduce production of SAA. less thanbrgreater than less thanbrgreater thanAs no structure for SAA is available we aim to perform an in silico assessment of its structural and fibrillation properties. In the paper we propose an ab initio model of the structure of SAA, which consists of a five membered helical bundle with a fold related to the tetratricopeptide repeat domain. As there are uncertainties relating to the packing of the helices, each helical region is subjected to triplicate molecular dynamics simulations to assess the integrity of the structural region. The first helix, stretching from residues 1 to 13, is the least stable according to the simulations: almost all of the helical conformation is lost during the 10 ns simulations, whereas the other helices maintain portions that remain in an helical conformation in at least 80% of the simulations. All helices are also subjected to a single 100 ns simulation to investigate how the secondary structure develops over time. In them helix 1 adopts a beta-hairpin structure similar to other fibril forming proteins. The beta-hairpin can in turn multimerise and form a mature fibril structure. The mechanism behind the conformational transition appears to be driven by interactions of side chains of charged residues, particularly Arginine 1. It exchanges interaction partners in the simulation and stabilizes intermediate conformations on the folding pathway to the final beta-hairpin.
Place, publisher, year, edition, pages
Elsevier , 2012. Vol. 39, 29-34 p.
Colonic amyloidosis, Amyloid A amyloidosis, Serum Amyloid A, Fibril, Molecular dynamics simulation, Ab initio structure prediction
Engineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-84355DOI: 10.1016/j.compbiolchem.2012.06.005ISI: 000308618600005OAI: oai:DiVA.org:liu-84355DiVA: diva2:558778