Jones EM, Surewicz WK.
Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids.
Cell. 2005 Apr 8;121(1):63-72.
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Why are prion proteins able to propagate in one species and not another? What happens during the rare events when strains of prion proteins are able to breach the species barrier? These critical questions, elegantly addressed by the recent papers from Surewicz and Weissman, may have structural answers with parallels to Alzheimer disease (AD).
One vexing problem in the field of prion biology is that strain-dependent differences at the amino acid level do not fully account for transmission specificity. The hypothesis that prion propagation is the result of specific conformational states influenced by, but not dependent on, primary amino acid sequence was tested in two separate sets of in vitro experiments. These groups characterized specific biophysical and structural properties of different strains of prion protein and related them to transmission specificity. Taken together, the results suggest that cross-species transmission is actually a propagation of protein conformation occurring between proteins that differ in primary sequence. Sequence may ultimately determine the range of conformations prion proteins can adopt, but the ability of the prion to propagate resides in the protein fold.
Although an equivalent infectious mechanism has never been established for AD, several parallels exist at the protein level between amyloid-β and prion proteins. Both proteins can undergo a transition from a soluble monomeric state to a polymerized amyloid fibril via a nucleation-dependent polymerization reaction. In addition, both proteins exhibit conformation-specific biological activities.
To determine how structural changes in prion proteins relate to transmission specificity, changes in protein structure were monitored using several complementary biophysical techniques by both groups and related to cross-species transmission. Some of the most striking evidence presented by Jones and Surewicz for the transmission of protein conformation occurring between different strains of prion proteins came from analysis of the fine morphological detail of the amyloid fibrils by atomic force microscopy (AFM). Changes in transmission specificity could be directly correlated with distinct fibril morphologies. It is tempting to speculate that a similar correlation exists for amyloid-β fibrils, also shown to exhibit similar smooth, beaded, and helical morphologies by AFM (Stine et al., 1996). Amyloid-β conformation has been shown to be strongly dependent on primary sequence and solution conditions (Stine et al., 2003), and these different protein conformations have distinct biological activities (Dahlgren et al., 2002). Changes in amyloid-β primary sequence associated with familial AD also influence both amyloid fibril assembly and fibril toxicity compared to wild-type fibrils (Dahlgren et al., 2002), paralleling the structural and functional differences observed with the “species-mimicking” point mutations in PrP23-144.
Changes in prion fibril morphology parallel changes in secondary structure as measured by Fourier transform infrared (FTIR) spectroscopy by Jones and Surewicz. Very similar conclusions are made by the Weissman group working with different strains of prion protein. Their results also relate prion transmission specificity to structural changes measured by FTIR, thermostability, and fine conformational detail by site-directed spin labeling-electron paramagnetic resonance (SDSL-EPR). (Although results from negative stain electron microscopy (EM) hint at a correlation between fibril morphology and transmission specificity). Both of these studies benefit from a robust functional measure for prion activity. Unfortunately for amyloid-β, a similar direct functional system currently does not exist and most assays depend on biological endpoints such as behavior testing, neurotoxicity, glial inflammation, or changes in LTP.
Identical protein folds can result from polypeptide chains that differ at the amino acid level and, conversely, identical primary sequences can assemble into distinct secondary, tertiary, and quaternary structures. The suggestion that for prion proteins (and possibly other amyloidogenic proteins), primary sequence only serves to provide boundaries for a pool of possible conformational states provides new insight into the perplexing question of amyloid structure-function. Strain-dependent prion propagation and cross-species prion transmission appear to have a structural foundation: the transmission of an infectious protein conformation.