Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z

Eisenhaber, Birgit; Sinha, Swati; Wong, Wing-Cheong; Eisenhaber, Frank

doi:10.1080/15384101.2018.1456294

Cited by 17 publications

(17 citation statements)

References 38 publications

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“…Three GPI-ETs (PIGN, PIGO and PIGG) are also multiple transmembrane proteins bearing catalytic sites within the luminal regions [67]. The bioinformatic study identified a common GPI recognition region in transmembrane domains of PIGW, PIGM, PIGV, PIGB, PIGZ, PIGN, PIGO and PIGG, and suggested a gene family comprising them [70].…”

Section: Biosynthetic Assembly Of Gpi Precursorsmentioning

confidence: 99%

Biosynthesis and biology of mammalian GPI-anchored proteins

2020

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At least 150 human proteins are glycosylphosphatidylinositol-anchored proteins (GPI-APs). The protein moiety of GPI-APs lacking transmembrane domains is anchored to the plasma membrane with GPI covalently attached to the C-terminus. The GPI consists of the conserved core glycan, phosphatidylinositol and glycan side chains. The entire GPI-AP is anchored to the outer leaflet of the lipid bilayer by insertion of fatty chains of phosphatidylinositol. Because of GPI-dependent membrane anchoring, GPI-APs have some unique characteristics. The most prominent feature of GPI-APs is their association with membrane microdomains or membrane rafts. In the polarized cells such as epithelial cells, many GPI-APs are exclusively expressed in the apical surfaces, whereas some GPI-APs are preferentially expressed in the basolateral surfaces. Several GPI-APs act as transcytotic transporters carrying their ligands from one compartment to another. Some GPI-APs are shed from the membrane after cleavage within the GPI by a GPI-specific phospholipase or a glycosidase. In this review, I will summarize the current understanding of GPI-AP biosynthesis in mammalian cells and discuss examples of GPI-dependent functions of mammalian GPI-APs.

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Section: Biosynthetic Assembly Of Gpi Precursorsmentioning

confidence: 99%

Biosynthesis and biology of mammalian GPI-anchored proteins

2020

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“…An incomplete list involves genetic screens, analysis of mutations in suitable model organisms, omics studies, cell biology work, structural biology research, sequence‐analytic comparisons (for example, as in ref. ), clinical applications, etc. The critical point is usually the discovery of biomolecular mechanisms, of enzymatic and binding activities, of critical conformational changes as well as of interactions with other biomacromolecules and small compounds.…”

Section: Introductionmentioning

confidence: 99%

Darkness in the Human Gene and Protein Function Space: Widely Modest or Absent Illumination by the Life Science Literature and the Trend for Fewer Protein Function Discoveries Since 2000

et al. 2018

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The mentioning of gene names in the body of the scientific literature 1901–2017 and their fractional counting is used as a proxy to assess the level of biological function discovery. A literature score of one has been defined as full publication equivalent (FPE), the amount of literature necessary to achieve one publication solely dedicated to a gene. It has been found that less than 5000 human genes have each at least 100 FPEs in the available literature corpus. This group of elite genes (4817 protein‐coding genes, 119 non‐coding RNAs) attracts the overwhelming majority of the scientific literature about genes. Yet, thousands of proteins have never been mentioned at all, ≈2000 further proteins have not even one FPE of literature and, for ≈4600 additional proteins, the FPE count is below 10. The protein function discovery rate measured as numbers of proteins first mentioned or crossing a threshold of accumulated FPEs in a given year has grown until 2000 but is in decline thereafter. This drop is partially offset by function discoveries for non‐coding RNAs. The full human genome sequencing does not boost the function discovery rate. Since 2000, the fastest growing group in the literature is that with at least 500 FPEs per gene.

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“…4. PIG-U (CDC91/GAB1 in yeast) [25], a protein with 10 transmembrane regions interconnected by loops, has the most likely function of shuttling the GPI lipid anchor and presenting it in a productive conformation to the transamidase complex and especially to GPAA1 [26]. 5.…”

Section: Pig-t (Gpi16p In Yeast) Is Predicted By Sequence Homology Tomentioning

confidence: 99%

Structural Modelling of the Lumenal Domain of Human GPAA1, the Metallo-Peptide Synthetase Subunit of the Transamidase Complex, Reveals Zinc-Binding Mode and Two Flaps Surrounding the Active Site

Su¹,

Sinha²,

Eisenhaber³

et al. 2020

Preprint

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Background The transamidase complex is a molecular machine in the endoplasmic reticulum of eukaryotes that attaches a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins after cleaving a C-terminal propeptide with a defined sequence signal. Its five subunits are very hydrophobic; thus, solubility, heterologous expression and complex reconstruction are difficult. Therefore, theoretical approaches are currently the main source of insight into details of 3D structure and of the catalytic process. Results In this work, we generated model 3D structures of the lumenal domain of human GPAA1, the M28-type metallo-peptide-synthetase subunit of the transamidase, including zinc ion and model substrate positions. In comparative molecular dynamics (MD) simulations of M28-type structures and our GPAA1 models, we estimated the metal ion binding energies with evolutionary conserved amino acid residues in the catalytic cleft. We find that canonical zinc binding sites 2 and 3 are strongest binders for Zn1 and, where a second zinc is available, sites 2 and 4 for Zn2. Zinc interaction of site 5 with Zn1 enhances upon substrate binding in structures with only one zinc. Whereas a previously studied glutaminyl cyclase structure, the best known homologue to GPAA1, binds only one zinc ion at the catalytic site, GPAA1 can sterically accommodate two. The M28-type metallopeptidases segregate into two independent branches with regard to one/two zinc ion binding modality in a phylogenetic tree where the GPAA1 family is closer to the joint origin of both groups. For GPAA1 models, MD studies revealed two large loops (flaps) surrounding the active site being involved in an anti-correlated, breathing-like dynamics. Conclusions In the light of combined sequence-analytic and phylogenetic arguments as well as 3D structural modelling results, GPAA1 is most likely a single zinc ion metallopeptidase. Two large flaps environ the catalytic site restricting access to large substrates.

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Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z

Cited by 17 publications

References 38 publications

Biosynthesis and biology of mammalian GPI-anchored proteins

Biosynthesis and biology of mammalian GPI-anchored proteins

Darkness in the Human Gene and Protein Function Space: Widely Modest or Absent Illumination by the Life Science Literature and the Trend for Fewer Protein Function Discoveries Since 2000

Structural Modelling of the Lumenal Domain of Human GPAA1, the Metallo-Peptide Synthetase Subunit of the Transamidase Complex, Reveals Zinc-Binding Mode and Two Flaps Surrounding the Active Site

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