Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human

Abstract

This article presents a comprehensive review of large and highly diverse superfamily of nucleotidyltransferase fold proteins by providing a global picture about their evolutionary history, sequence-structure diversity and fulfilled functional roles. Using top-of-the-line homology detection method combined with transitive searches and fold recognition, we revised the realm of these superfamily in numerous databases of catalogued protein families and structures, and identified 10 new families of nucleotidyltransferase fold. These families include hundreds of previously uncharacterized and various poorly annotated proteins such as Fukutin/LICD, NFAT, FAM46, Mab-21 and NRAP. Some of these proteins seem to play novel important roles, not observed before for this superfamily, such as regulation of gene expression or choline incorporation into cell membrane. Importantly, within newly detected families we identified 25 novel superfamily members in human genome. Among these newly assigned members are proteins known to be involved in congenital muscular dystrophy, neurological diseases and retinal pigmentosa what sheds some new light on the molecular background of these genetic disorders. Twelve of new human nucleotidyltransferase fold proteins belong to Mab-21 family known to be involved in organogenesis and development. The determination of specific biological functions of these newly detected proteins remains a challenging task.

FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta

“…FAM46A maps to human chromosome 6 and encompasses three exons which lead to a 5609 bp mRNA. The FAM46A transcript codes for a 442-amino-acid soluble protein of yet unknown function (http://www.ensembl.org) but that contains a recognised peptide domain between residues 66 and 383 (DUF1693; pfam07984 (NCBI)) reported to be part of the nucleotidyltransferase (NTase) fold superfamily of proteins 10. The FAM46A gene is also characterised by the presence of a variable number of tandem repeats (VNTR) within its coding sequence (exon 2) 11–13.…”

A census of human RNA-binding proteins

“…4Cb; see Supplementary information S4 (table)). RBDs and DNA-binding domains often originate from common superfamily folds, such as the oligonucleotide-binding fold (OB-fold), nucleotidyltransferase domains, zinc-finger domains, and DNA and RNA helicase domains34,43,89,90 . However, although TFs and RBPs have a shared evolutionary history, TFs expanded late in evolution into large families by multiple gene duplications58 , with up to 50 members per family and 2.5 members on average.…”

Essential Role of Yl MPO1 , a Novel Yarrowia lipolytica Homologue of Saccharomyces cerevisiae MNN4 , in Mannosylphosphorylation of N- and O-Linked Glycans

“…The predicted product of YALI0D24101g has a region with significant homology to the LicD domain found in the LICD protein family (PF04991), a member of recently identified groups of nucleotidyltransferase fold proteins. The LICD protein family includes ScMnn4p and bacterial LicD phosphotransferase which use GDP-mannose and CDP-choline as substrates, respectively (23). However, the Y. lipolytica homologue does not have at its C terminus the long KKKK EEEE repeat region, which has been reported to be an important domain for the function of ScMnn4p (32).…”