The early phase of the β2m aggregation mechanism: an integrative computational analysis based on the D76N mutant and ΔN6 variant
Protein beta-2-microglobulin (β2m) is the causative agent of dialysis related amyloidosis (DRA), which affects patients undergoing long-term (>10 years) hemodialysis. Furthermore, the D76N mutant is associated with a hereditary systemic amyloidosis affecting visceral organs. We carried out a comparative analysis of the early phase of aggregation of two natural variants of β2m, the D76N mutant and ΔN6 variant, to get insights into the early events triggering the β2m aggregation mechanism.
Folding simulations predict the existence of two intermediates in the D76N folding transition, one termed I1 featuring an unstructured and detached C-terminus and another termed I2, with both termini unstructured and detached. The intermediate I1 is topologically similar to the intermediate populated by ΔN6 in which the unstructured terminus is the N-terminus . Monte Carlo docking simulations indicate an essential role of the unstructured termini, as well as of the BC-, DE- and EF-loops in β2m aggregation . The termini tend to be more relevant in dimerization at acidic conditions while the BC-, DE- and EF-loops are the dominant regions at physiological pH. Moreover, results from simulations also corroborate experimental evidence according to which residues Tyr10 (A-strand), Phe30 and His31 (BC-loop), Trp60 and Phe62 (DE-loop) and Arg97 (C-terminus) play an important role in the aggregation mechanism of β2m . They further predict the occurrence of novel hot-spot residues, such as Lys-75 (EF-loop) and Trp-95 (C-terminus), i.e. new testable theoretical predictions to guide the research on β2-microglobulin amyloidogenesis.
 S Loureiro RJ, Vila-Viçosa D, Machuqueiro M, Shakhnovich EI, FN Faísca P. A tale of two tails: The importance of unstructured termini in the aggregation pathway of β2-microglobulin. Proteins. 2017;00:1–13.
 JS Loureiro R, Vila-Viçosa D, Machuqueiro M, Shakhnovich EI, FN Faísca P. The Early Phase of β2m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the ΔN6 Variant. Biomolecules. 2019, 9, 366.