Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding

Both oxidative stress and aggregation of the protein α-synuclein (aS) have been implicated as key factors in the etiology of Parkinson's disease. Specifically, oxidative modifications to aS disrupt its binding to lipid membranes, an interaction considered critical to its native function. Here we seek to provide a mechanistic explanation for this phenomenon by investigating the effects of oxidative nitration of tyrosine residues on the structure of aS and its interaction with lipid membranes. Membrane binding is mediated by the first ～95 residues of aS. We find that nitration of the single tyrosine (Y39) in this domain disrupts binding due to electrostatic repulsion. Moreover, we observe that nitration of the three tyrosines (Y125/133/136) in the C-terminal domain is equally effective in perturbing binding, an intriguing result given that the C-terminus is not thought to interact directly with the lipid bilayer. Our investigations show that tyrosine nitration results in a change of the conformational states populated by aS in solution, with the most prominent changes occurring in the C-terminal region. These results lead us to suggest that nitration of Y125/133/136 reduces the membrane-binding affinity of aS through allosteric coupling by altering the ensemble of conformational states and depopulating those capable of membrane binding. While allostery is a well-established concept for structured proteins, it has only recently been discussed in the context of disordered proteins. We propose that allosteric regulation through modification of specific residues in, or ligand binding to, the C-terminus may even be a general mechanism for modulating aS function.     

On the degree of approximation of functions belonging to a Lipschitz class by Hausdorff means of its fourier series

In a recent paper Lal and Yadov [4] obtained a theorem on the degree of approximation for a function belonging to the Lipschitz class Lipα using the product of the Cesàro and Euler means of order one of its Fourier series. In this paper we extend this result to any regular Hausdorff matrix for the same class of functions.     

Generalized uniform covering maps relative to subgroups

In “Rips complexes and covers in the uniform category” (Brodskiy et al., preprint [4]) the authors define, following James (1990) [5], covering maps of uniform spaces and introduce the concept of generalized uniform covering maps. Conditions for the existence of universal uniform covering maps and generalized uniform covering maps are given. This paper extends these results by investigating the existence of these covering maps relative to subgroups of the uniform fundamental group and the fundamental group of the base space.     

Spectra and Fine Spectra for Factorable Matrices

We obtain the spectra and fine spectra for factorable triangular matrices. Our results contain some previous work of the authors as special cases.     

On |A|k summability factors

Summary The paper deals with absolute summability factors for infinite series. The main result obtained in this paper generalizes a recent paper of Mazhar.     

Spectra for Factorable Matrices on ℓ p

We obtain the spectra and fine spectra for factorable matrices, considered as bounded linear operators over ℓ^p , 1 < p < ∞.     

A note on absolute summability factors

Summary We obtain sufficient conditions for the series <InlineEquation ID=IE"1"><EquationSource Format="TEX"><![CDATA[<InlineEquation ID=IE"2"><EquationSource Format="TEX"><![CDATA[<InlineEquation ID=IE"3"><EquationSource Format="TEX"><![CDATA[$]]></EquationSource></InlineEquation>]]></EquationSource></InlineEquation>]]></EquationSource></InlineEquation>\sum a_{n}\lambda_{n}$ to be absolutely summable of order $k$ by a<span lang=FR style='font-size:10.0pt; mso-ansi-language:FR'>triangular matrix.     

Temperley-Lieb Immanants

We use the Temperley-Lieb algebra to define a family of totally nonnegative polynomials of the form . The cone generated by these polynomials contains all totally nonnegative polynomials of the form , where, are matrix minors. We also give new conditions on the sets I,...,K′ which characterize differences of products of minors which are totally nonnegative. Received September 30, 2004