Summary: Putative GlcNAc-1 phosphotransferase regulatory domain

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Wikipedia: N-acetylglucosamine-1-phosphate transferase
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N-acetylglucosamine-1-phosphate transferase Edit Wikipedia article

N-acetylglucosamine-1-phosphate transferase, alpha and beta subunits
Identifiers
Symbol	GNPTAB
Alt. symbols	GNPTA
NCBI gene	79158
HGNC	29670
OMIM	607840
RefSeq	NM_024312
UniProt	Q3T906
Other data
Locus	Chr. 12 q23.3

N-acetylglucosamine-1-phosphate transferase, gamma subunit
Identifiers
Symbol	GNPTG
Alt. symbols	GNPTAG
NCBI gene	84572
HGNC	23026
OMIM	607838
RefSeq	NM_032520
UniProt	Q9UJJ9
Other data
Locus	Chr. 16 p13.3

N-acetylglucosamine-1-phosphate transferase is a transferase enzyme.

Function

It is made up of two alpha (Î±), two betas (Î²), and two gammas (Î³) subunits. GNPTAB produces the alpha and beta subunits, GNPTG produces the gamma subunit. GlcNAc-1-phosphotransferase functions to prepare newly made enzymes for lysosome transportation (lysosomal hydrolases to the lysosome). Lysosomes, a part of an animal cell, helps break down large molecules into smaller ones that can be reused. GlcNAc-1-phosphotransferase catalyzes the N-linked glycosylation of asparagine residues with a molecule called mannose-6-phosphate (M6P). M6P acts as an indicator of whether a hydrolase should be transported to the lysosome or not. Once a hydrolase indicates an M6P, it can be transported to a lysosome. Surprisingly some lysosomal enzymes are only tagged at a rate of 5% or lower.

Clinical significance

It is associated with the following conditions:^[1]^[2]

mucolipidosis II alpha/beta (I-cell disease) - GNPTAB
mucolipidosis III alpha/beta (pseudo-Hurler polydystrophy) - GNPTAB
mucolipidosis III gamma - GNPTG
stuttering (Kang et al., 2010)

In melanocytic cells, GNPTG gene expression may be regulated by MITF.^[3]

References

^ Online Mendelian Inheritance in Man (OMIM) MUCOLIPIDOSIS II ALPHA/BETA -252500
^ Online Mendelian Inheritance in Man (OMIM) MUCOLIPIDOSIS III GAMMA -252605
^ Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665â€“76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.

Kang, C., Riazuddin, S., Mundorff, J., Krasnewich, D., Friedman, P., Mullikin, J.C., and Drayna, D. (2010). Mutations in the Lysosomal Enzymeâ€“Targeting Pathway and Persistent Stuttering. New England Journal of Medicine 362, 677-685.

External links

GeneReviews/NCBI/NIH/UW entry on Mucolipidosis III Alpha/Beta
GeneReviews/NIH/NCBI/UW entry on Mucolipidosis II
GeneReviews/NIH/NCBI/UW entry on Mucolipidosis III Gamma
N-acetylglucosamine-1-phosphate+transferase at the US National Library of Medicine Medical Subject Headings (MeSH)
EC 2.7.8.15

Transferases: phosphorus-containing groups (EC 2.7)

2.7.1-2.7.4:
phosphotransferase/kinase
(PO₄)

2.7.1: OH acceptor	Hexo- Gluco- Fructo- Hepatic Galacto- Phosphofructo- 1 Liver Muscle Platelet 2 Riboflavin Shikimate Thymidine ADP-thymidine NAD⁺ Glycerol Pantothenate Mevalonate Pyruvate Deoxycytidine PFP Diacylglycerol Phosphoinositide 3 Class I PI 3 Class II PI 3 Sphingosine Glucose-1,6-bisphosphate synthase
2.7.2: COOH acceptor	Phosphoglycerate Aspartate kinase
2.7.3: N acceptor	Creatine
2.7.4: PO₄ acceptor	Phosphomevalonate Adenylate Nucleoside-diphosphate Uridylate Guanylate Thiamine-diphosphate

2.7.6: diphosphotransferase
(P₂O₇)

2.7.7: nucleotidyltransferase
(PO₄-nucleoside)

Polymerase

DNA polymerase	DNA-directed DNA polymerase I/A Î³ Î¸ Î½ T7 Taq II/B Î± Î´ Îµ Î¶ Pfu III/C IV/X Î² Î» Î¼ TDT V/Y Î· Î¹ Îº RNA-directed DNA polymerase Reverse transcriptase Telomerase
RNA nucleotidyltransferase	Template-directed RNA polymerase I II III IV V ssRNAP POLRMT Primase 1 2 PrimPol RNA-dependent RNA polymerase Polyadenylation PAP PNPase

Phosphorolytic
3' to 5' exoribonuclease

Nucleotidyltransferase

Guanylyltransferase

mRNA capping enzyme

Other

2.7.8: miscellaneous

Phosphatidyltransferases	CDP-diacylglycerolâ€”glycerol-3-phosphate 3-phosphatidyltransferase CDP-diacylglycerolâ€”serine O-phosphatidyltransferase CDP-diacylglycerolâ€”inositol 3-phosphatidyltransferase CDP-diacylglycerolâ€”choline O-phosphatidyltransferase
Glycosyl-1-phosphotransferase	N-acetylglucosamine-1-phosphate transferase

2.7.10-2.7.13: protein kinase
(PO₄; protein acceptor)

2.7.10: protein-tyrosine	see tyrosine kinases
2.7.11: protein-serine/threonine	see serine/threonine-specific protein kinases
2.7.12: protein-dual-specificity	see serine/threonine-specific protein kinases
2.7.13: protein-histidine	Protein-histidine pros-kinase Protein-histidine tele-kinase Histidine kinase

v t e Metabolism: carbohydrate metabolism · glycoprotein enzymes
Anabolism	Dolichol kinase GCS1 Oligosaccharyltransferase
Catabolism	Neuraminidase Beta-galactosidase Hexosaminidase mannosidase alpha-Mannosidase beta-mannosidase Aspartylglucosaminidase Fucosidase NAGA
Transport	SLC17A5
M6P tagging	N-acetylglucosamine-1-phosphate transferase

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Putative GlcNAc-1 phosphotransferase regulatory domain Provide feedback

The Golgi enzyme UDP-GlcNAc-lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase), an alpha2beta2gamma2 hexamer, mediates the initial step in the addition of the mannose 6-phosphate targeting signal on newly synthesized lysosomal enzymes [1]. GNPTAB encodes the alpha and beta subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III alpha-beta The alpha-beta subunits contain three identifiable domains separated by so-called spacer regions. This domain is part of the first spacer region, Spacer-1 [2]. Studies indicate that GlcNAc-1 lacking spacer-1 exhibits enhanced phosphorylation of several non-lysosomal glycoproteins, while the phosphorylation of lysosomal acid hydrolases is not altered. In view of these effects on the maturation and function of GlcNAc-1, it is suggested to rename 'spacer-1' the 'regulatory-1' domain [1].

Literature references

Liu L, Lee WS, Doray B, Kornfeld S;, FEBS Lett. 2017;591:47-55.: Role of spacer-1 in the maturation and function of GlcNAc-1-phosphotransferase. PUBMED:27981560 EPMC:27981560
Qian Y, van Meel E, Flanagan-Steet H, Yox A, Steet R, Kornfeld S;, J Biol Chem. 2015;290:3045-3056.: Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition. PUBMED:25505245 EPMC:25505245

This tab holds annotation information from the InterPro database.

InterPro entry IPR041536

The Golgi enzyme UDP-GlcNAc-lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase), an alpha2beta2gamma2 hexamer, mediates the initial step in the addition of the mannose 6-phosphate targeting signal on newly synthesized lysosomal enzymes [PUBMED:27981560]. GNPTAB encodes the alpha and beta subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III alpha-beta The alpha-beta subunits contain three identifiable domains separated by so-called spacer regions. This domain is part of the first spacer region, Spacer-1 [PUBMED:25505245]. Studies indicate that GlcNAc-1 lacking spacer-1 exhibits enhanced phosphorylation of several non-lysosomal glycoproteins, while the phosphorylation of lysosomal acid hydrolases is not altered. In view of these effects on the maturation and function of GlcNAc-1, it is suggested to rename 'spacer-1' the 'regulatory-1' domain [PUBMED:27981560].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan RRM (CL0221), which has the following description:

This clan contains families that are related to the RNA recognition motif domains. However, not all these families are RNA binding.

The clan contains the following 31 members:

BRAP2 Calcipressin DbpA DUF1743 DUF1866 DUF4523 GlcNAc-1_reg GUCT Limkain-b1 Nup35_RRM Nup35_RRM_2 PHM7_cyt RL RNA_bind RRM_1 RRM_2 RRM_3 RRM_5 RRM_7 RRM_8 RRM_9 RRM_occluded RRM_Rrp7 SET_assoc Smg4_UPF3 Spo7_2_N Tap-RNA_bind Transposase_22 U1snRNP70_N XS YlmH_RBD

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
UniProt: alignment generated by searching the UniProtKB sequence database using the family HMM
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

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Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (2)	Full (242)	Representative proteomes				UniProt (385)	NCBI (697)	Meta (0)
	Seed (2)	Full (242)	RP15 (20)	RP35 (59)	RP55 (173)	RP75 (266)	UniProt (385)	NCBI (697)	Meta (0)
Jalview	View	View	View	View	View	View	View	View
HTML	View	View
PP/heatmap	₁	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (2)	Full (242)	Representative proteomes				UniProt (385)	NCBI (697)	Meta (0)
	Seed (2)	Full (242)	RP15 (20)	RP35 (59)	RP55 (173)	RP75 (266)	UniProt (385)	NCBI (697)	Meta (0)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (2)	Full (242)	Representative proteomes				UniProt (385)	NCBI (697)	Meta (0)
	Seed (2)	Full (242)	RP15 (20)	RP35 (59)	RP55 (173)	RP75 (266)	UniProt (385)	NCBI (697)	Meta (0)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

ECOD:EUF06676

Previous IDs:

none

Type:

Domain

Sequence Ontology:

SO:0000417

Author:

El-Gebali S

Number in seed:

2

Number in full:

242

Average length of the domain:

85.60 aa

Average identity of full alignment:

73 %

Average coverage of the sequence by the domain:

7.37 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	26.4	26.4
Trusted cut-off	27.3	31.3
Noise cut-off	25.7	25.6

Model length:

88

Family (HMM) version:

2

Download:

download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

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Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GlcNAc-1_reg domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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Family: GlcNAc-1_reg (PF18440)

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