MetalPDB in 2018: a database of metal sites in biological macromolecular structures

Putignano, Valeria; Rosato, Antonio; Banci, Lucia; Andreini, Claudia

doi:10.1093/nar/gkx989

Cited by 178 publications

(177 citation statements)

References 17 publications

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“…The MetalPDB database contains information on all the MBPs and the Pfam domains found in structurally characterized metalloproteins. 9 Our search started from 352 Pfam domains: 261 with an associated iron-containing 3D structure (102 binding individual iron ions, 80 binding iron-sulfur clusters, and 79 binding heme) and 91 annotated as iron-binding domains. This search was integrated by locally searching from MBPs within all human protein sequences.…”

Section: Methodsmentioning

confidence: 99%

“…For sites binding individual iron ions the only other relevant function is its use as a substrate, i.e. in storage and transport processes (this classification of sites is taken from the MetalPDB database 9 ). Heme-binding sites have the largest variety of functional roles, among which electron transfer is the second most common.…”

Section: Subcellular Localization Of Human Iron-proteinsmentioning

confidence: 99%

“…Each iron ion is tetracoordinated, with its coordination sphere typically completed by the sulfur or nitrogen atoms of cysteine and histidine side chains, respectively. 9 The metal site of rubredoxin, which contains a single iron ion coordinated by four cysteines, is generally classified as the simplest unit of iron-sulfur clusters. Iron-sulfur clusters are among the most versatile inorganic cofactors.…”

Section: Introductionmentioning

confidence: 99%

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The human iron-proteome†

et al. 2018

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Organisms from all kingdoms of life use iron-proteins in a multitude of functional processes. We applied a bioinformatics approach to investigate the human portfolio of iron-proteins. We separated ironproteins based on the chemical nature of their metal-containing cofactors: individual iron ions, heme cofactors and iron-sulfur clusters. We found that about 2% of human genes encode an iron-protein.Of these, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. More than half of the human iron-proteins have a catalytic function. Indeed, we predict that 6.5% of all human enzymes are iron-dependent. This percentage is quite different for the various enzyme classes. Human oxidoreductases feature the largest fraction of iron-dependent family members (about 37%). The distribution of iron proteins in the various cellular compartments is uneven.In particular, the mitochondrion and the endoplasmic reticulum are enriched in iron-proteins with respect to the average content of the cell. Finally, we observed that genes encoding iron-proteins are more frequently associated to pathologies than the all other human genes on average. The present research provides an extensive overview of iron usage by the human proteome, and highlights several specific features of the physiological role of iron ions in human cells. Significance to metallomicsIron is one of the most ancient and abundant metal ions in living organisms: it participates in fundamental biological processes, such as photosynthesis, and respiration. It is an essential metal ion for humans. Here, we applied a bioinformatics approach to predict the entire set of human proteins that use iron as cofactor. We found that about 2% of human genes encode an iron-protein. In particular, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. Most of these proteins are enzymes: 37% of the human oxidoreductases need an iron ion to perform their catalytic mechanisms. The analysis of the subcellular location highlighted that some organelles are enriched in iron-proteins, in particular about 7% of the proteins localized in the endoplasmic reticulum and in the mitochondrion bind iron. Finally, our data show that mutations in genes encoding iron-binding proteins are more likely to be associated with pathology than all human genes on average.

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Section: Methodsmentioning

confidence: 99%

Section: Subcellular Localization Of Human Iron-proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The human iron-proteome†

et al. 2018

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“…3b), among others (Fig. S11-S13) (Putignano et al, 2018) . We sought to design calcium or nickel binding sites in the long state by introducing aspartic acid or histidine at the key hinge residue position.…”

Section: Tuning the Short/long State Difference In The Hinge Regionmentioning

confidence: 78%

Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds

Wei

Moschidi

Bick

et al. 2019

Preprint

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The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used to de novo design proteins that fold to a single state with a deep free energy minima (Huang et al., 2016) , and to reengineer natural proteins to alter their dynamics (Davey et al., 2017) or fold (Alexander et al., 2009) , the de novo design of closely related sequences which adopt well-defined, but structurally divergent structures remains an outstanding challenge. Here, we design closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations -one short (~66 Å height) and the other long (~100 Å height) -

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“…Among these, the most frequent mutation is E455K, which forms part of a calcium-binding site that is known to be crucial for ligand binding (29, 38). We used MetalPDB (38) to find the calcium-binding residues in the 2VJ3 structure (Fig. 3g, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Investigating structure function relationships in the NOTCH family through large-scale somatic DNA sequencing studies

Hall

Shorthouse

Jones

et al. 2020

Preprint

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The recent development of highly sensitive DNA sequencing techniques has detected large numbers of missense mutations of genes, including NOTCH1 and 2, in ageing normal tissues. Driver mutations persist and propagate in the tissue through a selective advantage over both wild-type cells and alternative mutations. This process of selection can be considered as a large scale, in vivo screen for mutations that increase clone fitness. It follows that the specific missense mutations that are observed in individual genes may offer us insights into the structure-function relationships. Here we show that the positively selected missense mutations in NOTCH1 and NOTCH2 in human oesophageal epithelium cause inactivation predominantly through protein misfolding. Once these mutations are excluded, we further find statistically significant evidence for selection at the ligand binding interface and calcium binding sites. In this, we observe stronger evidence of selection at the ligand interface on EGF12 over EGF11, suggesting that in this tissue EGF12 may play a more important role in ligand interaction. Finally, we show how a mutation hotspot in the NOTCH1 transmembrane helix arises through the intersection of both a high mutation rate and residue conservation. Together these insights offer a route to understanding the mechanism of protein function through in vivo mutant selection.

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MetalPDB in 2018: a database of metal sites in biological macromolecular structures

Cited by 178 publications

References 17 publications

The human iron-proteome†

The human iron-proteome†

Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds

Investigating structure function relationships in the NOTCH family through large-scale somatic DNA sequencing studies

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