Ahn, Hee-Chul Le, Yen T. H. Nagchowdhuri, Partha S. Derose, Eugene F. Putnam-Evans, Cindy London, Robert E. Markley, John L. Lim, Kwang Hun 2024-01-21T02:04:54Z 2024-01-21T02:04:54Z 2021-08-31 2006-11 0961-8368 https://pubs.kist.re.kr/handle/201004/135013 Amyloid formation is associated with structural changes of native polypeptides to monomeric intermediate states and their self-assembly into insoluble aggregates. Characterizations of the amyloidogenic intermediate state are, therefore, of great importance in understanding the early stage of amyloidogenesis. Here, we present NMR investigations of the structural and dynamic properties of the acid-unfolded amyloidogenic intermediate state of the phosphatidylinositol 3-kinase (PI3K) SH3 domain-a model peptide. The monomeric amyloidogenic state of the SH3 domain studied at pH 2.0 (35 degrees C) was shown to be substantially disordered with no secondary structural preferences. N-15 NMR relaxation experiments indicated that the unfolded polypeptide is highly flexible on a subnanosecond timescale when observed under the amyloidogenic condition (pH 2.0, 35 degrees C). However, more restricted motions were detected in residues located primarily in the beta-strands as well as in a loop in the native fold. In addition, nonnative long-range interactions were observed between the residues with the reduced flexibility by paramagnetic relaxation enhancement (PRE) experiments. These indicate that the acid-unfolded state of the SH3 domain adopts a partly folded conformation through nonnative long-range contacts between the dynamically restricted residues at the amyloid-forming condition. English COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT 8 M UREA FIBRIL FORMATION SH3 DOMAIN PROTEIN AGGREGATION ALPHA-SYNUCLEIN PI3-SH3 DOMAIN UNFOLDED STATE DYNAMICS BETA(2)-MICROGLOBULIN INTERMEDIATE NMR characterizations of an amyloidogenic conformational ensemble of the PI3KSH3 domain Article 10.1110/ps.062154306 1 PROTEIN SCIENCE, v.15, no.11, pp.2552 - 2557 PROTEIN SCIENCE 15 11 2552 2557 scie scopus 000241666600010 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article DYNAMICS BETA(2)-MICROGLOBULIN INTERMEDIATE 8 M UREA FIBRIL FORMATION SH3 DOMAIN PROTEIN AGGREGATION ALPHA-SYNUCLEIN PI3-SH3 DOMAIN UNFOLDED STATE amyloids PI3KSH3 NMR dynamics amyloidogenic intermediate long-range interactions PRE