Biochemistry and Pharmacology - Research Publications

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Subject: Biochemistry and Cell Biology not elsewhere classified ; Biological Sciences × Author: Perugini, Matthew ×

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    The 2.1 Å crystal structure of the far-red fluorescent protein HcRed: Inherent conformational flexibility of the chromophore
    Wilmann, PG ; Petersen, J ; Pettikiriarachchi, A ; Buckle, AM ; Smith, SC ; Olsen, S ; Perugini, MA ; Devenish, RJ ; Prescott, M ; Rossjohn, J (Elsevier BV, 2005-05-27)
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    Non-fibrillar components of amyloid deposits mediate the self-association and tangling of amyloid fibrils
    MacRaild, CA ; Stewart, CR ; Mok, YF ; Gunzburg, MJ ; Perugini, MA ; Lawrence, LJ ; Tirtaatmadja, V ; Cooper-White, JJ ; Howlett, GJ (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004-05-14)
    Amyloid deposits are proteinaceous extra-cellular aggregates associated with a diverse range of disease states. These deposits are composed predominantly of amyloid fibrils, the unbranched, beta-sheet rich structures that result from the misfolding and subsequent aggregation of many proteins. In addition, amyloid deposits contain a number of non-fibrillar components that interact with amyloid fibrils and are incorporated into the deposits in their native folded state. The influence of a number of the non-fibrillar components in amyloid-related diseases is well established; however, the mechanisms underlying these effects are poorly understood. Here we describe the effect of two of the most important non-fibrillar components, serum amyloid P component and apolipoprotein E, upon the solution behavior of amyloid fibrils in an in vitro model system. Using analytical ultracentrifugation, electron microscopy, and rheological measurements, we demonstrate that these non-fibrillar components cause soluble fibrils to condense into localized fibrillar aggregates with a greatly enhanced local density of fibril entanglements. These results suggest a possible mechanism for the observed role of non-fibrillar components as mediators of amyloid deposition and deposit stability.
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    A biophysical analysis of the tetratricopeptide repeat-rich mitochondrial import receptor, Tom70, reveals an elongated monomer that is inherently flexible, unstable, and unfolds via a multistate pathway
    Beddoe, T ; Bushell, SR ; Perugini, MA ; Lithgow, T ; Mulhern, TD ; Bottomley, SP ; Rossjohn, J (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004-11-05)
    Proteins destined for all submitochondrial compartments are translocated across the outer mitochondrial membrane by the TOM (translocase of the outer membrane) complex, which consists of a number of specialized receptor subunits that bind mitochondrial precursor proteins for delivery into the translocation channel. One receptor, Tom70, binds large, hydrophobic mitochondrial precursors. The current model of Tom70-mediated import involves multiple dimers of the receptor recognizing a single molecule of substrate. Here we show via a battery of biophysical and spectroscopic techniques that the cytosolic domain of Tom70 is an elongated monomer. Thermal and urea-induced denaturation revealed that the receptor, which unfolds via a multistate pathway, is a relatively unstable molecule undergoing major conformational change at physiological temperatures. The data suggest that the malleability of the monomeric Tom70 receptor is an important factor in mitochondrial import.