TY - JOUR
T1 - Conformational changes associated with L16P and T118M mutations in the membrane-embedded PMP22 protein, consequential in CMT-1A
AU - Bello, Martiniano
AU - Torres, Mixtli J.
AU - Méndez-Tenorio, Alfonso
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2017/10/3
Y1 - 2017/10/3
N2 - Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is required for myelin formation in the peripheral nervous system. Excess PMP22 mutants accumulate in the endoplasmic reticulum (ER) resulting in the inherited neuropathies of Charcot–Marie–Tooth disease. However, there was no evidence of the structure of PMP22 or how mutations affect its folding. Therefore, in this study, we combined bioinformatics and homology modeling approaches to obtain three-dimensional native and mutated PMP22 models and its anchoring to a POPC membrane, submitted to.5-μs MD simulations, to determine how the L16P and T118M mutations affect the conformational behavior of PMP22. In addition, we investigated the ability of the native and mutated species to accumulate in the ER, via interaction with RER1, by combining protein–protein docking and MD simulations, taking the conformations that were most representative of the native and mutated PMP22 systems and RER1 conformations. Principal component analysis over MD simulations revealed that L16P and T118M mutations resulted in increased structural instability compared to the native form, which is consistent with previous experimental findings of increased structural fluctuations along a loop connecting transmembrane α-helix1 and α-helix2. Docking and MD simulations coupled with the MMGBSA approach allowed the identification that the binding interface for the PMP22-RER1 complex takes place through transmembrane α-helix1 and α-helix2, with higher effective binding free energy values between the mutated PMP22 systems and RER1 than for the native PMP22, mainly through van der Waals interactions.
AB - Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is required for myelin formation in the peripheral nervous system. Excess PMP22 mutants accumulate in the endoplasmic reticulum (ER) resulting in the inherited neuropathies of Charcot–Marie–Tooth disease. However, there was no evidence of the structure of PMP22 or how mutations affect its folding. Therefore, in this study, we combined bioinformatics and homology modeling approaches to obtain three-dimensional native and mutated PMP22 models and its anchoring to a POPC membrane, submitted to.5-μs MD simulations, to determine how the L16P and T118M mutations affect the conformational behavior of PMP22. In addition, we investigated the ability of the native and mutated species to accumulate in the ER, via interaction with RER1, by combining protein–protein docking and MD simulations, taking the conformations that were most representative of the native and mutated PMP22 systems and RER1 conformations. Principal component analysis over MD simulations revealed that L16P and T118M mutations resulted in increased structural instability compared to the native form, which is consistent with previous experimental findings of increased structural fluctuations along a loop connecting transmembrane α-helix1 and α-helix2. Docking and MD simulations coupled with the MMGBSA approach allowed the identification that the binding interface for the PMP22-RER1 complex takes place through transmembrane α-helix1 and α-helix2, with higher effective binding free energy values between the mutated PMP22 systems and RER1 than for the native PMP22, mainly through van der Waals interactions.
KW - PMP22
KW - binding free energy calculations
KW - charcot–marie–tooth
KW - docking
KW - molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=84990200598&partnerID=8YFLogxK
U2 - 10.1080/07391102.2016.1234415
DO - 10.1080/07391102.2016.1234415
M3 - Artículo
C2 - 27609586
SN - 0739-1102
VL - 35
SP - 2880
EP - 2894
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 13
ER -