TY - JOUR

T1 - The conformational and mutational landscape of the ubiquitin-like marker for autophagosome formation in cancer

AU - Fas, Burcu Aykac

AU - Maiani, Emiliano

AU - Sora, Valentina

AU - Kumar, Mukesh

AU - Mashkoor, Maliha

AU - Lambrughi, Matteo

AU - Tiberti, Matteo

AU - Papaleo, Elena

PY - 2021

Y1 - 2021

N2 - Macroautophagy/autophagy is a cellular process to recycle damaged cellular components, and its modulation can be exploited for disease treatments. A key autophagy player is the ubiquitin-like protein MAP1LC3B/LC3B. Mutations and changes in MAP1LC3B expression occur in cancer samples. However, the investigation of the effects of these mutations on MAP1LC3B protein structure is still missing. Despite many LC3B structures that have been solved, a comprehensive study, including dynamics, has not yet been undertaken. To address this knowledge gap, we assessed nine physical models for biomolecular simulations for their capabilities to describe the structural ensemble of MAP1LC3B. With the resulting MAP1LC3B structural ensembles, we characterized the impact of 26 missense mutations from pan-cancer studies with different approaches, and we experimentally validated our prediction for six variants using cellular assays. Our findings shed light on damaging or neutral mutations in MAP1LC3B, providing an atlas of its modifications in cancer. In particular, P32Q mutation was found detrimental for protein stability with a propensity to aggregation. In a broader context, our framework can be applied to assess the pathogenicity of protein mutations or to prioritize variants for experimental studies, allowing to comprehensively account for different aspects that mutational events alter in terms of protein structure and function.

AB - Macroautophagy/autophagy is a cellular process to recycle damaged cellular components, and its modulation can be exploited for disease treatments. A key autophagy player is the ubiquitin-like protein MAP1LC3B/LC3B. Mutations and changes in MAP1LC3B expression occur in cancer samples. However, the investigation of the effects of these mutations on MAP1LC3B protein structure is still missing. Despite many LC3B structures that have been solved, a comprehensive study, including dynamics, has not yet been undertaken. To address this knowledge gap, we assessed nine physical models for biomolecular simulations for their capabilities to describe the structural ensemble of MAP1LC3B. With the resulting MAP1LC3B structural ensembles, we characterized the impact of 26 missense mutations from pan-cancer studies with different approaches, and we experimentally validated our prediction for six variants using cellular assays. Our findings shed light on damaging or neutral mutations in MAP1LC3B, providing an atlas of its modifications in cancer. In particular, P32Q mutation was found detrimental for protein stability with a propensity to aggregation. In a broader context, our framework can be applied to assess the pathogenicity of protein mutations or to prioritize variants for experimental studies, allowing to comprehensively account for different aspects that mutational events alter in terms of protein structure and function.

KW - Autophagy

KW - cancer mutations

KW - MAP1LC3B

KW - molecular dynamics

KW - protein structure network

KW - structural alphabets

U2 - 10.1080/15548627.2020.1847443

DO - 10.1080/15548627.2020.1847443

M3 - Journal article

C2 - 33302793

VL - 17

SP - 2818

EP - 2841

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 10

ER -