TY - JOUR
T1 - Exploring the conformational space of Bcl-2 protein variants
T2 - Dynamic contributions of the flexible loop domain and transmembrane region
AU - Caro-Gómez, Luis A.
AU - Rosas-Trigueros, Jorge L.
AU - Mixcoha, Edgar
AU - Vique-Sánchez, José L.
AU - Gasperin-Sánchez, Humberto
AU - Benítez-Cardoza, Claudia G.
AU - Zamorano-Carrillo, Absalom
N1 - Publisher Copyright:
© 2019 by the authors.
PY - 2019
Y1 - 2019
N2 - Members of the Bcl-2 protein family regulate apoptosis through interactions with several proteins. A critical intrinsically disordered region (IDR) present in some members of the Bcl-2 family is essential for their function. Also, the structural and conformational plasticity of disordered regions is essential for the regulation of the Bcl-2 protein’s activity. Further, some proteins of the family contain transmembrane-helical regions, which anchor them into organelle membranes. Bcl-2, the archetypical member of the family, is characterized by an IDR labeled as a flexible loop domain (FLD) and a transmembrane domain (TMD). Another member of this family is the Bcl-2A1 protein, containing a TMD but lacking the FLD. To our knowledge, this is the first report which characterizes the individual and simultaneous dynamical contributions of FLD and TMD in Bcl-2 and Bcl-2A1 using molecular dynamics simulations (MDS). We examined the conformational spaces of Bcl-2, Bcl-2A1, and two artificial constructs lacking the TMD (Bcl-2∆TM and Bcl-2A1∆TM). As the results show, FLD and TMD stabilized each protein independently when they are present. When they coincided, such as in Bcl-2, an additive stabilizing effect is observed. This information is crucial for understanding the structural mechanisms of interaction in the Bcl-2 family.
AB - Members of the Bcl-2 protein family regulate apoptosis through interactions with several proteins. A critical intrinsically disordered region (IDR) present in some members of the Bcl-2 family is essential for their function. Also, the structural and conformational plasticity of disordered regions is essential for the regulation of the Bcl-2 protein’s activity. Further, some proteins of the family contain transmembrane-helical regions, which anchor them into organelle membranes. Bcl-2, the archetypical member of the family, is characterized by an IDR labeled as a flexible loop domain (FLD) and a transmembrane domain (TMD). Another member of this family is the Bcl-2A1 protein, containing a TMD but lacking the FLD. To our knowledge, this is the first report which characterizes the individual and simultaneous dynamical contributions of FLD and TMD in Bcl-2 and Bcl-2A1 using molecular dynamics simulations (MDS). We examined the conformational spaces of Bcl-2, Bcl-2A1, and two artificial constructs lacking the TMD (Bcl-2∆TM and Bcl-2A1∆TM). As the results show, FLD and TMD stabilized each protein independently when they are present. When they coincided, such as in Bcl-2, an additive stabilizing effect is observed. This information is crucial for understanding the structural mechanisms of interaction in the Bcl-2 family.
KW - Apoptosis regulation
KW - Bcl-2
KW - Bcl-2A1
KW - Flexible loop domain
KW - Intrinsically disordered region
KW - Molecular dynamics simulation
KW - Transmembrane domain
UR - http://www.scopus.com/inward/record.url?scp=85074354692&partnerID=8YFLogxK
U2 - 10.3390/molecules24213896
DO - 10.3390/molecules24213896
M3 - Artículo
C2 - 31671865
SN - 1420-3049
VL - 24
JO - Molecules
JF - Molecules
IS - 21
M1 - 3896
ER -