Noninteracting local-structure model of folding and unfolding transition in globular proteins. I. Formulation

Biopolymers ◽  
1981 ◽  
Vol 20 (5) ◽  
pp. 991-1011 ◽  
Author(s):  
Nobuhiro G? ◽  
Haruo Abe
Keyword(s):  
Local Structure ◽  
Globular Proteins ◽  
Structure Model

scholarly journals A clinically-relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat position

2020 ◽  
Author(s):  
Melissa J. Ruggiero ◽  
Shipra Malhotra ◽  
Aron W. Fenton ◽  
Liskin Swint-Kruse ◽  
John Karanicolas ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Integral Membrane Protein ◽  
Surface Expression ◽  
Globular Proteins ◽  
Model Structure ◽  
Structure Model ◽  
Software Suite ◽  
Functional Changes ◽  
Functional Studies ◽  
Altered Transport

AbstractConventionally, most amino acid substitutions at important protein positions are expected to abolish function. However, in several soluble-globular proteins, we identified a class of non-conserved positions for which various substitutions produced progressive functional changes; we consider these evolutionary “rheostats”. Here, we report a strong rheostat position in the integral membrane protein, Na+/taurocholate cotransporting polypeptide (NTCP), at the site of a pharmacologically-relevant polymorphism (S267F). Functional studies were performed for all 20 substitutions (“S267X”) with three substrates (taurocholate, estrone-3-sulfate and rosuvastatin). The S267X set showed strong rheostatic effects on overall transport, and individual substitutions showed varied effects on transport kinetics (Km and Vmax). However, the outcomes were substrate dependent, indicating altered specificity. To assess protein stability, we measured surface expression and used the Rosetta software suite to model structure and stability changes of S267X. Although buried near the substrate binding site, S267X substitutions were easily accommodated in the NTCP structure model. Across the modest range of changes, calculated stabilities correlated with surface-expression differences, but neither parameter correlated with altered transport. Thus, substitutions at rheostat position 267 had wide-ranging effects on the phenotype of this integral membrane protein. We further propose that polymorphic positions in other proteins might be locations of rheostat positions.

Local-structure model ofK+site inKTaO3:Fe3+

1990 ◽  
Vol 42 (1) ◽  
pp. 917-919 ◽  
Author(s):  
Zhou Yi-Yang
Keyword(s):  
Local Structure ◽  
Structure Model

scholarly journals Folding process of threedimensional lattice proteins by nointeracting local structure model

2001 ◽  
Vol 41 (supplement) ◽  
pp. S172
Author(s):  
H Abe ◽  
K Tashiro ◽  
F Kano ◽  
H Wako
Keyword(s):  
Local Structure ◽  
Structure Model ◽  
Folding Process ◽  
Lattice Proteins

scholarly journals A clinically-relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat position

2020 ◽  
pp. jbc.RA120.014889
Author(s):  
Melissa J. Ruggiero ◽  
Shipra Malhotra ◽  
Aron W. Fenton ◽  
Liskin Swint-Kruse ◽  
John Karanicolas ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Integral Membrane Protein ◽  
Surface Expression ◽  
Globular Proteins ◽  
Model Structure ◽  
Structure Model ◽  
Software Suite ◽  
Functional Changes ◽  
Functional Studies ◽  
Altered Transport

Conventionally, most amino acid substitutions at important protein positions are expected to abolish function. However, in several soluble-globular proteins, we identified a class of non-conserved positions for which various substitutions produced progressive functional changes; we consider these evolutionary “rheostats”. Here, we report a strong rheostat position in the integral membrane protein, Na+/taurocholate cotransporting polypeptide (NTCP), at the site of a pharmacologically-relevant polymorphism (S267F). Functional studies were performed for all 20 substitutions (“S267X”) with three substrates (taurocholate, estrone-3-sulfate and rosuvastatin). The S267X set showed strong rheostatic effects on overall transport, and individual substitutions showed varied effects on transport kinetics (Km and Vmax) and substrate specificity. To assess protein stability, we measured surface expression and used the Rosetta software suite to model structure and stability changes of S267X. Although buried near the substrate binding site, S267X substitutions were easily accommodated in the NTCP structure model. Across the modest range of changes, calculated stabilities correlated with surface-expression differences, but neither parameter correlated with altered transport. Thus, substitutions at rheostat position 267 had wide-ranging effects on the phenotype of this integral membrane protein. We further propose that polymorphic positions in other proteins might be locations of rheostat positions.

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