TY - JOUR
T1 - Synonymous Mutations and Ribosome Stalling Can Lead to Altered Folding Pathways and Distinct Minima
AU - Tsai, Chung Jung
AU - Sauna, Zuben E.
AU - Kimchi-Sarfaty, Chava
AU - Ambudkar, Suresh V.
AU - Gottesman, Michael M.
AU - Nussinov, Ruth
N1 - Funding Information:
The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services; neither does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number N01-CO-12400. This research was supported in part by the Intramural Research Program of the Center for Cancer Research of the National Cancer Institute, National Institutes of Health. We thank Dr. H. Robert Guy (Laboratory of Cell Biology, National Cancer Institute) for comments on the manuscript.
PY - 2008/11/7
Y1 - 2008/11/7
N2 - How can we understand a case in which a given amino acid sequence folds into structurally and functionally distinct molecules? Synonymous single-nucleotide polymorphisms in the MDR1 (multidrug resistance 1 or ABCB1) gene involving frequent-to-rare codon substitutions lead to identical protein sequences. Remarkably, these alternative sequences give a protein product with similar but different structures and functions. Here, we propose that long-enough ribosomal pause time scales may lead to alternate folding pathways and distinct minima on the folding free energy surface. While the conformational and functional differences between the native and alternate states may be minor, the MDR1 case illustrates that the barriers may nevertheless constitute sufficiently high hurdles in physiological time scales, leading to kinetically trapped states with altered structures and functions. Different folding pathways leading to conformationally similar trapped states may be due to swapping of (fairly symmetric) segments. Domain swapping is more likely in the no-pause case in which the chain elongates and folds simultaneously; on the other hand, sufficiently long pause times between such segments may be expected to lessen the chances of swapping events. Here, we review the literature in this light.
AB - How can we understand a case in which a given amino acid sequence folds into structurally and functionally distinct molecules? Synonymous single-nucleotide polymorphisms in the MDR1 (multidrug resistance 1 or ABCB1) gene involving frequent-to-rare codon substitutions lead to identical protein sequences. Remarkably, these alternative sequences give a protein product with similar but different structures and functions. Here, we propose that long-enough ribosomal pause time scales may lead to alternate folding pathways and distinct minima on the folding free energy surface. While the conformational and functional differences between the native and alternate states may be minor, the MDR1 case illustrates that the barriers may nevertheless constitute sufficiently high hurdles in physiological time scales, leading to kinetically trapped states with altered structures and functions. Different folding pathways leading to conformationally similar trapped states may be due to swapping of (fairly symmetric) segments. Domain swapping is more likely in the no-pause case in which the chain elongates and folds simultaneously; on the other hand, sufficiently long pause times between such segments may be expected to lessen the chances of swapping events. Here, we review the literature in this light.
KW - ABC transporter
KW - kinetics
KW - multidrug resistance gene
KW - protein folding
KW - synonymous mutations
UR - http://www.scopus.com/inward/record.url?scp=52949137359&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2008.08.012
DO - 10.1016/j.jmb.2008.08.012
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AN - SCOPUS:52949137359
SN - 0022-2836
VL - 383
SP - 281
EP - 291
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -