Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, Zweckstetter M. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1430-5. PubMed.
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EPFL/ND BioSciences
α-synuclein is frequently described as a “natively unfolded” or random coil protein (i.e., it exists in an ensemble of unordered conformations in vitro). Two papers published in the last two weeks, including the one by Bertoncini et al., provide more evidence that the structure of α-synuclein is not so random. The data from both groups show that α-synuclein exists as an ensemble of conformations ranging from extended to rather compact. Using a combination of NMR techniques (paramagnetic relaxation enhancement (PRE) and NMR dipolar couplings) and molecular dynamics, the two groups show that long-range intramolecular interactions play an important role in stabilizing the native conformations of α-synuclein and preventing its aggregation. These long-range interactions involve the C-terminal and the hydrophobic region in the middle of the protein, known as the NAC region, which has a high propensity to aggregate, forms amyloid fibrils both in vitro and in vivo, and is thought to drive α-synuclein aggregation. Both groups proposed that shielding of this aggregation-prone region by the C-terminus prevents aggregation of α-synuclein. These results are consistent with previous observations demonstrating that deleting or sequestering (via binding to polyamines) the C-terminus of α-synuclein accelerates its aggregation in vitro, implying an inhibitory role for this region of the protein. It will be very interesting to see whether the Parkinson disease-associated mutations (A53T, A30P and E46K), which are known to accelerate the oligomerization and/or fibrillization of α-synuclein in vitro, exert their effects by disrupting such long-range interactions.
It is noteworthy that David Eliezer and coworkers have previously proposed that α-synuclein is stabilized by the existence of residual or transient structures (found only 10 percent of the time) in its native conformations. Using NMR techniques, the researchers identified a residual helical structure in the N-terminal region of wild-type α-synuclein, which is perturbed or abolished by the disease-associated mutant A30P that is known to accelerate α-synuclein oligomerization. The model proposed by Eliezer and coworkers suggests that interactions between this transient helical segment and the hydrophobic NAC region would interfere with key intermolecular interactions involved in the early stages of α-synuclein aggregation.
Native state stabilization has been shown to be an effective strategy for inhibiting the aggregation of natively folded amyloidogenic proteins in vitro. The assumption that unordered amyloidogenic proteins such as α-synuclein lack a defined structure or hydrophobic pockets has led many in the field to rule out such a strategy for inhibiting α-synuclein aggregation. However, the identification of long-range interactions and residual structures in the native conformations of α-synuclein, which seem to play a role in modulating its aggregation properties, is likely to prompt renewed interest in native state stabilization as a potential strategy for preventing or reversing α-synuclein aggregation in Parkinson disease.
References:
Dedmon MM, Lindorff-Larsen K, Christodoulou J, Vendruscolo M, Dobson CM. Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations. J Am Chem Soc. 2005 Jan 19;127(2):476-7. PubMed.
Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, Zweckstetter M. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1430-5. PubMed.
Bussell R, Eliezer D. Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein. J Biol Chem. 2001 Dec 7;276(49):45996-6003. PubMed.
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