The conformational and mutational landscape of the ubiquitin-like marker for autophagosome formation in cancer
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The conformational and mutational landscape of the ubiquitin-like marker for autophagosome formation in cancer. / Fas, Burcu Aykac; Maiani, Emiliano; Sora, Valentina; Kumar, Mukesh; Mashkoor, Maliha; Lambrughi, Matteo; Tiberti, Matteo; Papaleo, Elena.
In: Autophagy, Vol. 17, No. 10, 2021, p. 2818-2841.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 253781051