Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations.
Autophagy
; 16(2): 239-255, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-30982432
ABSTRACT
Autophagy is a conserved adaptive cellular pathway essential to maintain a variety of physiological functions. Core components of this machinery are the six human Atg8 orthologs that initiate formation of appropriate protein complexes. While these proteins are routinely used as indicators of autophagic flux, it is presently not possible to discern their individual biological functions due to our inability to predict specific binding partners. In our attempts towards determining downstream effector functions, we developed a computational pipeline to define structural determinants of human Atg8 family members that dictate functional diversity. We found a clear evolutionary separation between human LC3 and GABARAP subfamilies and also defined a novel sequence motif responsible for their specificity. By analyzing known protein structures, we observed that functional modules or microclusters reveal a pattern of intramolecular network, including distinct hydrogen bonding of key residues (F52/Y49; a subset of HP2) that may directly modulate their interaction preferences. Multiple molecular dynamics simulations were performed to characterize how these proteins interact with a common protein binding partner, PLEKHM1. Our analysis showed remarkable differences in binding modes via intrinsic protein dynamics, with PLEKHM1-bound GABARAP complexes showing less fluctuations and higher number of contacts. We further mapped 373 genomic variations and demonstrated that distinct cancer-related mutations are likely to lead to significant structural changes. Our findings present a quantitative framework to establish factors underlying exquisite specificity of human Atg8 proteins, and thus facilitate the design of precise modulators.Abbreviations Atg autophagy-related; ECs evolutionary constraints; GABARAP GABA type A receptor-associated protein; HsAtg8 human Atg8; HP hydrophobic pocket; KBTBD6 kelch repeat and BTB domain containing 6; LIR LC3-interacting region; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MD molecular dynamics; HIV-1 Nef human immunodeficiency virus type 1 negative regulatory factor; PLEKHM1 pleckstrin homology and RUN domain containing M1; RMSD root mean square deviation; SQSTM1/p62 sequestosome 1; WDFY3/ALFY WD repeat and FYVE domain containing 3.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Reguladoras de Apoptose
/
Proteínas Associadas aos Microtúbulos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Autophagy
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Índia