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The left-handed parallel beta helix (LbetaH) fold has recently received attention as a possible structure for the prion protein (PrP) in its misfolded state. In light of this interest, we have developed an experimental system to examine the structural requirements of the LbetaH fold, using a known LbetaH protein, UDP-N-acetylglucosamine acyltransferase (LpxA), from E. coli. We showed that the beta helix can tolerate nonhydrophobic residues at interior positions and prolines were important, but not critical, in folding of the beta helix. Using our structural studies of the LbetaH, we threaded the sequence of the amyloidogenic fragment of the prion protein (residues 104-143) onto the structure of LpxA. Based on the threading result, we constructed the recombinant PrP-LpxA and tested its functional activity in an E. coli antibiotic sensitivity assay. The results of these experiments suggest that the amyloidogenic PrP fragment may fold into a beta helix in the context of a larger beta-helical structure., Journal Article, Research Support, N.I.H. Extramural, SCOPUS: ar.j, info:eu-repo/semantics/published

The left-handed parallel beta-helix (LbetaH) is a structurally repetitive, highly regular, and symmetrical fold formed by coiling of elongated beta-sheets into helical "rungs." This canonical fold has recently received interest as a possible solution to the fibril structure of amyloid and as a building block of self-assembled nanotubular structures. In light of this interest, we aimed to understand the structural requirements of the LbetaH fold. We first sought to determine the sequence characteristics of the repeats by analyzing known structures to identify positional preferences of specific residues types. We then used molecular dynamics simulations to demonstrate the stabilizing effect of successive rungs and the hydrophobic core of the LbetaH. We show that a two-rung structure is the minimally stable LbetaH structure. In addition, we defined the structure-based sequence preference of the LbetaH and undertook a genome-wide sequence search to determine the prevalence of this unique protein fold. This profile-based LbetaH search algorithm predicted a large fraction of LbetaH proteins from microbial origins. However, the relative number of predicted LbetaH proteins per specie was approximately equal across the genomes from prokaryotes to eukaryotes., Journal Article, Research Support, N.I.H. Extramural, SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published