Counting the Zinc-Proteins Encoded in the Human Genome

Abstract

Metalloproteins are proteins capable of binding one or more metal ions, which may be required for their biological function, or for regulation of their activities or for structural purposes. Genome sequencing projects have provided a huge number of protein primary sequences, but, even though several different elaborate analyses and annotations have been enabled by a rich and ever-increasing portfolio of bioinformatic tools, metal-binding properties remain difficult to predict as well as to investigate experimentally. Consequently, the present knowledge about metalloproteins is only partial. The present bioinformatic research proposes a strategy to answer the question of how many and which proteins encoded in the human genome may require zinc for their physiological function. This is achieved by a combination of approaches, which include: (i) searching in the proteome for the zinc-binding patterns that, on their turn, are obtained from all available X-ray data; (ii) using libraries of metal-binding protein domains based on multiple sequence alignments of known metalloproteins obtained from the Pfam database; and (iii) mining the annotations of human gene sequences, which are based on any type of information available. It is found that 1684 proteins in the human proteome are independently identified by all three approaches as zinc-proteins, 746 are identified by two, and 777 are identified by only one method. By assuming that all proteins identified by at least two approaches are truly zinc-binding and inspecting the proteins identified by a single method, it can be proposed that ca. 2800 human proteins are potentially zinc-binding in vivo, corresponding to 10% of the human proteome, with an uncertainty of 400 sequences. Available functional information suggests that the large majority of human zinc-binding proteins are involved in the regulation of gene expression. The most abundant class of zinc-binding proteins in humans is that of zinc-fingers, with Cys4 and Cys2His2 being the most common types of coordination environment.

Recognition of polyadenosine RNA by zinc finger proteins

“…With the identification of a zinc finger protein that displays poly(A) binding, the repertoire of this family of proteins has expanded. Given that zinc finger domains are one of the most abundant domains found in the human genome (42), this finding raises the possibility that there are additional pro- Fig. 3.…”

Probing the Structural Basis of Zn2+ Regulation of the Epithelial Na+ Channel

“…Zinc is the second most abundant transition metal in living organisms and is thought to complex with ϳ10% of the human proteome (21). It has catalytic, structural, or regulatory roles in proteins that are involved in diverse biological processes (22).…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…Although worldwide research on genetic variation that requires a different RDA or UL is still in progress, several genes and alleles have been suggested to affect nutrient utilization, including genes involved in the metabolism of folate and vitamin B-12 [60,62,91], lipids [61,74] alcohol [20], lactose [142], iron [46,77] and zinc [31,97]. In the context of healthy lifespan and longevity, nutrigenetic and nutrigenomic implications around this last nutrient (zinc) appear very important taking into account that: (1) RDA (11 mg/day for men and 8 mg/day for women) and UL (40 mg/day for adults) for zinc are very close [50]; (2) About 10% of the human proteome consists in potential Znbinding proteins [5]; (3) Proteins devoted to Zn transport (ZnT) and buffering, most of which display functional polymorphic sites, include at least ten members of the ZnT family [134], 15 members of the ZIP family (i.e. Zn-regulated metal transporter, iron-regulated metal transporterlike protein) [36,134] and ten distinct isoforms of MT [150]; 4) zinc is an essential micronutrient strictly involved in regulating gene expression [35], inflammatory response [63,124] and antioxidant activity [125].…”