Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Reports 5, 781-790 (2013).
The maintenance of protein solubility is a fundamental aspect of cellular homeostasis because protein aggregation is associated with a wide variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or aging. A crucial question in this context is why only certain proteins appear to aggregate readily in vivo, whereas others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. We find that these supersaturated proteins represent a metastable subproteome involved in pathological aggregation during stress and aging and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging.
Atomic structure and hierarchical assembly of a cross-beta amyloid fibril.
PNAS 110, 5468-5473 (2013).
The cross-beta amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of beta-sheet filaments. These complex aggregates have remarkable chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-beta amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale - including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryo-electron microscopy, scanning transmission electron microscopy, and atomic force microscopy - we report the atomic-resolution (0.5 A) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent beta-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils.
Determination of secondary structure populations in disordered states of proteins using NMR chemical shifts.
C. Camilloni, A. De Simone, W. Vranken and M. Vendruscolo. Biochemistry 51, 2224-2231 (2012).
Prediction of the aggregation propensity of proteins from their folded states.
G. G. Tartaglia, A. P. Pawar, S. Campioni, F. Chiti, C. M. Dobson and M. Vendruscolo. J. Mol. Biol. 380, 425-436 (2008)