TY - JOUR
T1 - Deciphering the Alphabet of Disorder-Glu and Asp Act Differently on Local but Not Global Properties
AU - Roesgaard, Mette Ahrensback
AU - Lundsgaard, Jeppe E.
AU - Newcombe, Estella A.
AU - Jacobsen, Nina L.
AU - Pesce, Francesco
AU - Tranchant, Emil E.
AU - Lindemose, Søren
AU - Prestel, Andreas
AU - Hartmann-Petersen, Rasmus
AU - Lindorff-Larsen, Kresten
AU - Kragelund, Birthe B.
PY - 2022
Y1 - 2022
N2 - Compared to folded proteins, the sequences of intrinsically disordered proteins (IDPs) are enriched in polar and charged amino acids. Glutamate is one of the most enriched amino acids in IDPs, while the chemically similar amino acid aspartate is less enriched. So far, the underlying functional differences between glutamates and aspartates in IDPs remain poorly understood. In this study, we examine the differential effects of aspartate and glutamates in IDPs by comparing the function and conformational ensemble of glutamate and aspartate variants of the disordered protein Dss1, using a range of assays, including interaction studies, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and molecular dynamics simulation. First, we analyze the sequences of the rapidly growing database of experimentally verified IDPs (DisProt) and show that glutamate enrichment is not caused by a taxonomy bias in IDPs. From analyses of local and global structural properties as well as cell growth and protein-protein interactions using a model acidic IDP from yeast and three Glu/Asp variants, we find that while the Glu/Asp variants support similar function and global dimensions, the variants differ in their binding affinities and population of local transient structural elements. We speculate that these local structural differences may play roles in functional diversity, where glutamates can support increased helicity, important for folding and binding, while aspartates support extended structures and form helical caps, as well as playing more relevant roles in, e.g., transactivation domains and ion-binding.
AB - Compared to folded proteins, the sequences of intrinsically disordered proteins (IDPs) are enriched in polar and charged amino acids. Glutamate is one of the most enriched amino acids in IDPs, while the chemically similar amino acid aspartate is less enriched. So far, the underlying functional differences between glutamates and aspartates in IDPs remain poorly understood. In this study, we examine the differential effects of aspartate and glutamates in IDPs by comparing the function and conformational ensemble of glutamate and aspartate variants of the disordered protein Dss1, using a range of assays, including interaction studies, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and molecular dynamics simulation. First, we analyze the sequences of the rapidly growing database of experimentally verified IDPs (DisProt) and show that glutamate enrichment is not caused by a taxonomy bias in IDPs. From analyses of local and global structural properties as well as cell growth and protein-protein interactions using a model acidic IDP from yeast and three Glu/Asp variants, we find that while the Glu/Asp variants support similar function and global dimensions, the variants differ in their binding affinities and population of local transient structural elements. We speculate that these local structural differences may play roles in functional diversity, where glutamates can support increased helicity, important for folding and binding, while aspartates support extended structures and form helical caps, as well as playing more relevant roles in, e.g., transactivation domains and ion-binding.
KW - Dss1
KW - intrinsically disordered protein
KW - IDPs
KW - molecular dynamics
KW - NMR
KW - sequence composition
KW - SAXS
KW - PROTEIN SECONDARY STRUCTURE
KW - FREE-ENERGY LANDSCAPES
KW - INTRINSIC DISORDER
KW - PROTEASOME
KW - EFFICIENT
KW - DYNAMICS
KW - SPECTROSCOPY
KW - PROPENSITY
KW - SCATTERING
KW - PARTICLE
U2 - 10.3390/biom12101426
DO - 10.3390/biom12101426
M3 - Journal article
C2 - 36291634
VL - 12
JO - Biomolecules
JF - Biomolecules
SN - 2218-273X
IS - 10
M1 - 1426
ER -