Evolution of EF-hand calcium-modulated proteins. II. Domains of several subfamilies have diverse evolutionary histories

Nakayama, Seiko; Moncrief, Nancy D.; Kretsinger, Robert H.

doi:10.1007/bf00162998

Cited by 157 publications

(122 citation statements)

References 84 publications

(56 reference statements)

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“…5D). This result agrees well with prior findings on the independent evolutionary past of EF-hand subfamilies (62). It is also interesting that the above TERM appears to correspond to the most structurally conserved portion of the EF hand and excludes the binding loop and much of the N-terminal helix (Fig.…”

Section: A Small Number Of Terms Describe Most Of the Structural Univsupporting

confidence: 92%

Tertiary alphabet for the observable protein structural universe

Mackenzie

Zhou

Grigoryan

2016

Proc. Natl. Acad. Sci. U.S.A.

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Here, we systematically decompose the known protein structural universe into its basic elements, which we dub tertiary structural motifs (TERMs). A TERM is a compact backbone fragment that captures the secondary, tertiary, and quaternary environments around a given residue, comprising one or more disjoint segments (three on average). We seek the set of universal TERMs that capture all structure in the Protein Data Bank (PDB), finding remarkable degeneracy. Only ∼600 TERMs are sufficient to describe 50% of the PDB at sub-Angstrom resolution. However, more rare geometries also exist, and the overall structural coverage grows logarithmically with the number of TERMs. We go on to show that universal TERMs provide an effective mapping between sequence and structure. We demonstrate that TERM-based statistics alone are sufficient to recapitulate close-to-native sequences given either NMR or X-ray backbones. Furthermore, sequence variability predicted from TERM data agrees closely with evolutionary variation. Finally, locations of TERMs in protein chains can be predicted from sequence alone based on sequence signatures emergent from TERM instances in the PDB. For multisegment motifs, this method identifies spatially adjacent fragments that are not contiguous in sequence-a major bottleneck in structure prediction. Although all TERMs recur in diverse proteins, some appear specialized for certain functions, such as interface formation, metal coordination, or even water binding. Structural biology has benefited greatly from previously observed degeneracies in structure. The decomposition of the known structural universe into a finite set of compact TERMs offers exciting opportunities toward better understanding, design, and prediction of protein structure.tertiary motif | structural degeneracy | protein structural universe | sequence-structure relationships | structural modularity I n this work, we aim to decompose the protein structure space into its basic elements as a way of understanding its design principles and describing its limits. Reductionist representations of protein structure have been of long-standing interest (1), with many studies having shown degeneracy at various structural levels (2-5). Features ranging from backbone or side-chain dihedral angles (6, 7) to domains and folds (8, 9) have been classified, and structural basins of attraction have been found in select motifs (10-17), offering a glimpse of a modular space with frequently repeating elements. The reason behind this modularity appears to be a combination of evolutionary history and the fundamental physics of structure. In particular, degeneracy at the level of domains, folds, and functional modules is likely strongly influenced by evolution, whereby such elements recur in different proteins often because of a common ancestor (18,19). On the other hand, statistics of more detailed structural features are better explained from the thermodynamic perspective. For example, observed Ramachandran backbone dihedral angle preferences are largely determined...

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Section: A Small Number Of Terms Describe Most Of the Structural Univsupporting

confidence: 92%

Tertiary alphabet for the observable protein structural universe

Mackenzie

Zhou

Grigoryan

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The EF-hands in CaM domains are odd-even paired with EF-hands 1 and 2 in nCaM and EF-hands 3 and 4 in cCaM. This arrangement of EF-hands in CaM is thought to be a consequence of its evolution from a biologically related ancestor EF-hand by gene duplication (38). The even-odd pairing of EF-hands 2 and 3 (CaM2/3) (Fig.…”

Section: Discussionmentioning

confidence: 98%

Inherent flexibility determines the transition mechanisms of the EF-hands of calmodulin

Tripathi

Portman

2009

Proc. Natl. Acad. Sci. U.S.A.

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We explore how inherent flexibility of a protein molecule influences the mechanism controlling allosteric transitions by using a variational model inspired from work in protein folding. The striking differences in the predicted transition mechanism for the opening of the two domains of calmodulin (CaM) emphasize that inherent flexibility is key to understanding the complex conformational changes that occur in proteins. In particular, the Cterminal domain of CaM (cCaM), which is inherently less flexible than its N-terminal domain (nCaM), reveals ''cracking'' or local partial unfolding during the open/closed transition. This result is in harmony with the picture that cracking relieves local stresses caused by conformational deformations of a sufficiently rigid protein. We also compare the conformational transition in a recently studied even-odd paired fragment of CaM. Our results rationalize the different relative binding affinities of the EF-hands in the engineered fragment compared with the intact odd-even paired EF-hands (nCaM and cCaM) in terms of changes in flexibility along the transition route. Aside from elucidating general theoretical ideas about the cracking mechanism, these studies also emphasize how the remarkable intrinsic plasticity of CaM underlies conformational dynamics essential for its diverse functions.T o understand protein function, it is often essential to characterize large conformational changes that occur upon ligand binding. Within the population shift mechanism of allosteric conformational change (1), the bound complex is formed when a ligand selects and stabilizes a weakly populated conformational ensemble from the kinetically accessible states of the unbound folded protein. Such conformational dynamics imply an inherent flexibility or ''intrinsic plasticity'' of the folded state. In this article, we focus on how this inherent flexibility of a protein molecule influences the mechanism controlling the kinetics of allosteric transitions. There are a couple of possible scenarios for the transition mechanism in terms of changes in conformational flexibility. One possibility is that the flexibility adjusts smoothly to conformational deformations connecting two specific metastable states in the free-energy surface. In this case, the inherent flexibility of the protein remains relatively constant if the metastable states have similar flexibilities or else changes smoothly between the flexibilities of the metastable states if the flexibilities are different. An alternative mechanism, called ''cracking'' (2), has recently been proposed. In terms of conformational f lexibility, cracking involves nonmonotonic changes in flexibility along the transitions route. In particular, the flexibility of specific regions of the protein may transiently increase through local unfolding. As explained in ref. 2, local unfolding can relieve specific areas of high stress during conformational deformations that would result in high free-energy barriers if the protein remained uniformly folded throughout the transi...

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“…EF-1 has 31 residues in the consensus sequence (14 residues in the calcium-binding loop) and binds Ca 2+ mainly through main-chain carbonyl O atoms (Nakayama et al, 1992). EF-1 has low af®nity for calcium compared with calmodulin and troponin C and indeed compared with S100 EF-2 (Kligman & Hilt, 1988).…”

Section: Introductionmentioning

confidence: 99%

The three-dimensional structure of human S100A12

Moroz

Antson

Murshudov

et al. 2001

Acta Crystallogr D Biol Cryst

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The crystal structure of human EF-hand calcium-binding protein S100A12 in its calcium-bound form has been determined to 1.95 A Ê resolution by molecular replacement using the structure of the S100B protein. The S100 family members are homologous to calmodulin and other related EF-hand calcium-binding proteins. Like the majority of S100 proteins, S100A12 is a dimer, with the interface between the two subunits being composed mostly of hydrophobic residues. The fold of S100A12 is similar to the other known crystal and solution structures of S100 proteins, except for the linker region between the two EF-hand motifs. Sequence and structure comparison between members of the S100 family suggests that the target-binding region in S100A12 is formed by the linker region and C-terminal residues of one subunit and the N-terminal residues of another subunit of the dimer. The N-terminal region of the target-binding site includes two glutamates that are conserved in most of the S100 sequences. The comparison also provided a better understanding of the role of the residues important for intra-and inter-subunit hydrophobic interactions. The precise role of S100A12 in cell behaviour is yet unde®ned, as is the case for the whole family, although it has been shown that the interaction of S100A12 with the RAGE receptor is implicated in in¯ammatory response.

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Evolution of EF-hand calcium-modulated proteins. II. Domains of several subfamilies have diverse evolutionary histories

Cited by 157 publications

References 84 publications

Tertiary alphabet for the observable protein structural universe

Tertiary alphabet for the observable protein structural universe

Inherent flexibility determines the transition mechanisms of the EF-hands of calmodulin

The three-dimensional structure of human S100A12

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