Structural and functional diversity of EF‐hand proteins: Evolutionary perspectives

Kawasaki, Hiroshi; Kretsinger, Robert H.

doi:10.1002/pro.3233

Cited by 88 publications

(63 citation statements)

References 47 publications

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“…PAP1‐a was a heterodimer formed by the association of S100A1‐α and S100B‐β subunits, whereas PAP1‐b was a homodimer of two S100B‐β subunits. Chemical sequencing of the S100A1‐α and S100B‐β subunits showed that they were members of the EF‐hand calcium‐binding superfamily of proteins that includes calmodulin, troponin C and parvalbumin (Isobe & Okuyama, , ); (Kawasaki & Kretsinger, ). Studies on the physico‐chemical and structural properties of the brain homodimers S100A1 and S100B and of the heterodimer S100A1/S100B confirmed Ca 2+ binding and revealed specific high‐affinity binding of Zn 2+ by the S100B protein (Baudier & Gerard, , ; Baudier et al ., ; Baudier, Labourdette & Gerard, ; Baudier, Glasser & Gerard, ).…”

Section: Introductionmentioning

confidence: 99%

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

2020

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The S100 genes encode a conserved group of 21 vertebrate-specific EF-hand calcium-binding proteins. Since their discovery in 1965, S100 proteins have remained enigmatic in terms of their cellular functions. In this review, we summarize the calcium-and zinc-binding properties of the dimeric S100B and S100A1 proteins and highlight data that shed new light on the extracellular and intracellular regulation and functions of S100B. We point out that S100B and S100A1 homodimers are not functionally interchangeable and that in a S100A1/S100B heterodimer, S100A1 acts as a negative regulator for the ability of S100B to bind Zn 2+ . The Ca 2+ and Zn 2+ -dependent interactions of S100B with a wide array of proteins form the basis of its activities and have led to the derivation of some initial rules for S100B recognition of protein targets. However, recent findings have strongly suggested that these rules need to be revisited. Here, we describe a new consensus S100B binding motif present in intracellular and extracellular vertebrate-specific proteins and propose a new model for stable interactions of S100B dimers with full-length target proteins. A chaperone-associated function for intracellular S100B in adaptive cellular stress responses is also discussed. This review may help guide future studies on the functions of S100 proteins in general.Biological Reviews 95 (2020) 738-758

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Section: Introductionmentioning

confidence: 99%

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

2020

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“…In conclusion, the M48K mutation does not affect the expression of FKBP22 in the rER but leads to an FKBP22 with weakened functions. Here we show that a partial loss of function leads to a similar phenotype as the complete loss of FKBP22 even though M48K FKBP22 could still have fully functional EF hand motifs, the function of which is mostly unknown except for binding calcium 30,31 . The molecular findings are in keeping with the clinical findings of the homozygous M48K patient which were similar to these of FKBP22 null patients 7 .…”

Section: Scientific Reports |mentioning

confidence: 83%

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

Ishikawa

Mizuno

Holden

et al. 2020

Sci Rep

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Mutations in the FKBP14 gene encoding FKBP22 (FK506 Binding Protein 22 kDa) cause kyphoscolioticEhlers-Danlos Syndrome (kEDS). The first clinical report showed that a lack of FKBP22 protein due to mutations causing nonsense-mediated decay of the mRNA leads to a wide spectrum of clinical phenotypes including progressive kyphoscoliosis, joint hypermobility, hypotonia, hyperelastic skin, hearing loss and aortic rupture. Our previous work showed that these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens. We also showed that FKBP22 catalyzed the folding of type III collagen through its prolyl isomerase activity and acted as a molecular chaperone for type III collagen. Recently, a novel missense mutation Met48Lys in FKBP22 was identified in a patient with kEDS. In this report, we expand the list of substrates of FKBP22 and also demonstrate that the Met48Lys mutation diminishes the activities of FKBP22, indicating that pathology can arise from absence of FKBP22, or partial loss of its function.Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder mainly characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Thirteen subtypes were classified in the 2017 EDS Nosology 1 and the kyphoscoliotic EDS (kEDS) was recognized as one subtype demonstrating a broader clinical spectrum of phenotypes with major and minor defined criteria. Congenital hypotonia, congenital or early onset kyphoscoliosis, and generalized joint hypermobility with dislocations/subluxations are the major features, and the minor features include skin hyperextensibility, easily bruised skin, rupture/aneurysm of a medium-sized arteries, and osteopenia/osteoporosis among others 1 . While the musculoskeletal symptoms are found in disorders caused by mutations in extracellular matrix (ECM) proteins, in particular collagen which is the most abundant protein in humans 2,3 , kEDS results from the deficiency of two proteins participating in collagen biosynthesis in the rough Endoplasmic Reticulum (rER): the post-translational modifying enzyme Lysyl Hydroxylase 1 (LH1 encoded by PLOD1) 4,5 and the peptidyl-prolyl cis/trans isomerase (PPIase) family protein FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14) 6,7 . The lack of these proteins changes the collagen biosynthetic molecular ensemble in the rER 8-10 , which can lead to the secretion of structurally and/or functionally abnormal collagens 11,12 . Therefore, EDS causative mutations are not restricted to genes coding for ECM molecules but also include genes coding for proteins required for ECM biosynthesis and processing.Proteins are biosynthesized inside the cells following the central dogma that protein information stored in DNA is first transcribed to messenger RNA (mRNA) which is then translated into protein 13,14 . Missense mutations affect this central dogma and alter protein biogenesis in different ways. Depending upon the location of the mu...

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“…In particular, ICAP2 is nearly twice as long as its mammalian counterparts and appears to have an EF-like domain in its N terminus. EF domains bind cations like Ca 2+ or Mg 2+ and can act to modulate protein-protein interactions or enzymatic activity (Kawasaki & Kretsinger, 2017). The mitochondrial matrix is known to act as a Ca 2+ store, and the presence of an EF-like domain suggests that ATP synthase activity may be somehow coordinated with mitochondrial Ca 2+ .…”

Section: Discussionmentioning

confidence: 99%

Identification of cryptic stator subunits from an apicomplexan ATP synthase

Huet

Rajendran

Dooren

et al. 2018

Preprint

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The mitochondrial ATP synthase is a macromolecular motor that uses the proton gradient to generate ATP. Proper ATP synthase function requires a stator linking the catalytic and rotary portions of the complex. However, sequence-based searches fail to identify genes encoding stator subunits in apicomplexan parasites like Toxoplasma gondii or the related organisms that cause malaria. Here, we identify 11 previously unknown subunits from the Toxoplasma ATP synthase, which lack homologs outside the phylum. Hidden Markov modeling suggests that two of them-ICAP2 and ICAP18-share distant homology with mammalian stator subunits. Our analysis shows that both proteins form part of the ATP synthase complex. Depletion of ICAP2 leads to aberrant mitochondrial morphology, decreased oxygen consumption, and disassembly of the complex, consistent with its role as an essential component of the Toxoplasma ATP synthase. Our findings highlight divergent features of the central metabolic machinery in apicomplexans, which may reveal new therapeutic opportunities.

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Structural and functional diversity of EF‐hand proteins: Evolutionary perspectives

Cited by 88 publications

References 47 publications

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

Identification of cryptic stator subunits from an apicomplexan ATP synthase

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Structural and functional diversity of EF‐hand proteins: Evolutionary perspectives

Cited by 88 publications

References 47 publications

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

Identification of cryptic stator subunits from an apicomplexan ATP synthase

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The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths