Dataset Information

Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.

ABSTRACT: Neuroserpin is a regulator of neuronal growth and plasticity. Like other members of the serpin family, neuroserpin undergoes a large conformational change as part of its function. Unlike other serpins such as α(1)-antitrypsin, wild-type neuroserpin will polymerize under near-physiological conditions, and will spontaneously transition to the latent state. To probe the origins of this conformational lability, we have performed hydrogen exchange measurements and molecular-dynamics simulations on human neuroserpin. Hydrogen exchange indicates that neuroserpin has greater flexibility in the breach region and in β-strand 1C compared with α(1)-antitrypsin. Molecular-dynamics simulations show that the distance between the top of β-strands 3 and 5A averages 4.6 Å but becomes as large as 7.5 Å in neuroserpin while it remains stable at ∼3.5 Å in α(1)-antitrypsin. Further simulations show that the stabilizing S340A mutation suppresses these fluctuations in neuroserpin. The first principal component calculated from the simulations shows a movement of helix F away from the face of β-sheet A in neuroserpin while no such movement is evident in α(1)-antitrypsin. The increased mobility of these regions in neuroserpin relative to α(1)-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.

SUBMITTER: Sarkar A

PROVIDER: S-EPMC3183757 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.

Sarkar Anindya A Zhou Crystal C Meklemburg Robert R Wintrode Patrick L PL

Biophysical journal 20111001 7

Neuroserpin is a regulator of neuronal growth and plasticity. Like other members of the serpin family, neuroserpin undergoes a large conformational change as part of its function. Unlike other serpins such as α(1)-antitrypsin, wild-type neuroserpin will polymerize under near-physiological conditions, and will spontaneously transition to the latent state. To probe the origins of this conformational lability, we have performed hydrogen exchange measurements and molecular-dynamics simulations on hu ...[more]

PMID: 21961602

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Project description:Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate - the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP), which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of alpha-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen Receptor ligand-binding domain, the RIP deformation map is quite sparse except for one large conformational change involving Helix-12, which is the structural element that allosterically links ligand binding to receptor activation. RIP analysis has the potential to discover sites of functional conformational changes and the linchpin residues critical in determining these conformational states.

Dataset Information

Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.

Publications

Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.

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