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Protein

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase

Gene

NAGPA

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the second step in the formation of the mannose 6-phosphate targeting signal on lysosomal enzyme oligosaccharides by removing GlcNAc residues from GlcNAc-alpha-P-mannose moieties, which are formed in the first step. Also hydrolyzes UDP-GlcNAc, a sugar donor for Golgi N-acetylglucosaminyltransferases.1 Publication

Catalytic activityi

Glycoprotein N-acetyl-D-glucosaminyl-phospho-D-mannose + H2O = N-acetyl-D-glucosamine + glycoprotein phospho-D-mannose.

Pathwayi: protein glycosylation

This protein is involved in the pathway protein glycosylation, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein glycosylation and in Protein modification.

GO - Molecular functioni

  • N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase activity Source: ProtInc

GO - Biological processi

  • carbohydrate metabolic process Source: ProtInc
  • cellular protein modification process Source: ProtInc
  • lysosome organization Source: ProtInc
  • protein glycosylation Source: UniProtKB-UniPathway
  • protein targeting to lysosome Source: ProtInc
  • secretion of lysosomal enzymes Source: Ensembl

Keywordsi

Molecular functionHydrolase

Enzyme and pathway databases

BRENDAi3.1.4.45. 2681.
UniPathwayiUPA00378.

Names & Taxonomyi

Protein namesi
Recommended name:
N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (EC:3.1.4.45)
Alternative name(s):
Mannose 6-phosphate-uncovering enzyme
Phosphodiester alpha-GlcNAcase
Gene namesi
Name:NAGPA
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:17378. NAGPA.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini50 – 448LumenalSequence analysisAdd BLAST399
Transmembranei449 – 469HelicalSequence analysisAdd BLAST21
Topological domaini470 – 515CytoplasmicSequence analysisAdd BLAST46

GO - Cellular componenti

  • Golgi cisterna membrane Source: UniProtKB-SubCell
  • integral component of membrane Source: ProtInc
  • integral component of plasma membrane Source: GO_Central

Keywords - Cellular componenti

Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Defects in NAGPA have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi51C → M: 65% of wild-type of activity. 1 Publication1
Mutagenesisi115C → S: 15% of wild-type of activity, and almost no traffic to Golgi. 1 Publication1
Mutagenesisi132C → V: No traffic to Golgi. 1 Publication1
Mutagenesisi137N → A: 11% of wild-type of activity. 1 Publication1
Mutagenesisi221C → L: 10% of wild-type of activity; when associated with M-51. 1 Publication1
Mutagenesisi225Q → H: 6% of wild-type of activity. 1 Publication1
Mutagenesisi227T → R: Complete loss of activity. 1 Publication1
Mutagenesisi247R → A: 87% of wild-type of activity. 1 Publication1
Mutagenesisi284N → A: 22% of wild-type of activity. 1 Publication1
Mutagenesisi286D → A: Complete loss of activity. 1 Publication1
Mutagenesisi287G → A: 16% of wild-type of activity. 1 Publication1
Mutagenesisi288G → A: Complete loss of activity. 1 Publication1
Mutagenesisi289G → A: Complete loss of activity. 1 Publication1
Mutagenesisi290S → A: Complete loss of activity. 1 Publication1
Mutagenesisi320T → A: 43% of wild-type of activity. 1 Publication1
Mutagenesisi322V → A: 67% of wild-type of activity. 1 Publication1
Mutagenesisi486Y → A: Interaction with AP4M1 is abolished. 1 Publication1
Mutagenesisi488Y → A: Interaction with AP4M1 is abolished. 1 Publication1
Mutagenesisi491L → A: Interaction with AP4M1 is abolished. 1 Publication1

Organism-specific databases

DisGeNETi51172.
MalaCardsiNAGPA.
OpenTargetsiENSG00000103174.
PharmGKBiPA134940049.

Chemistry databases

ChEMBLiCHEMBL5920.
DrugBankiDB00141. N-Acetyl-D-glucosamine.

Polymorphism and mutation databases

BioMutaiNAGPA.
DMDMi296439239.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 251 PublicationAdd BLAST25
PropeptideiPRO_000042465926 – 49Removed in mature formAdd BLAST24
ChainiPRO_000002178850 – 515N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidaseAdd BLAST466

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi115 ↔ 1481 Publication
Disulfide bondi132 ↔ 323PROSITE-ProRule annotation1 Publication
Glycosylationi208N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi214N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi296N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi307 ↔ 3141 Publication
Disulfide bondi362 ↔ 373PROSITE-ProRule annotation
Glycosylationi366N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi380 ↔ 389PROSITE-ProRule annotation
Glycosylationi388N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi420N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

The precursor is cleaved and activated in the trans-Golgi network by a furin endopeptidase.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Zymogen

Proteomic databases

EPDiQ9UK23.
PaxDbiQ9UK23.
PeptideAtlasiQ9UK23.
PRIDEiQ9UK23.

PTM databases

iPTMnetiQ9UK23.
PhosphoSitePlusiQ9UK23.

Expressioni

Tissue specificityi

Isoform 2 may be brain-specific.

Gene expression databases

BgeeiENSG00000103174.
CleanExiHS_NAGPA.
ExpressionAtlasiQ9UK23. baseline and differential.
GenevisibleiQ9UK23. HS.

Organism-specific databases

HPAiHPA064055.

Interactioni

Subunit structurei

Homotetramer arranged as two disulfide-linked homodimers. Interacts with AP4M1.By similarity1 Publication

Protein-protein interaction databases

BioGridi119351. 15 interactors.
IntActiQ9UK23. 2 interactors.
STRINGi9606.ENSP00000310998.

Structurei

3D structure databases

ProteinModelPortaliQ9UK23.
SMRiQ9UK23.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini358 – 390EGF-likePROSITE-ProRule annotationAdd BLAST33

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni486 – 493Mediates the interaction with AP4M11 Publication8

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi488 – 491Tyrosine-based internalization motif4
Motifi511 – 515NPF internalization motif5

Domaini

The tyrosine-based internalization signal may be essential for its retrieval from the plasma membrane to the TGN.
The C-terminal NPFKD sequence is an attractive candidate for either an endocytosis signal acting at the plasma membrane or a retrieval signal acting at the TGN to return the enzyme to the cis/medial-Golgi.

Keywords - Domaini

EGF-like domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IF19. Eukaryota.
ENOG410ZT6Y. LUCA.
GeneTreeiENSGT00730000111213.
HOGENOMiHOG000059612.
HOVERGENiHBG052571.
InParanoidiQ9UK23.
KOiK01125.
OMAiPSDHCQD.
OrthoDBiEOG091G05YS.
PhylomeDBiQ9UK23.
TreeFamiTF331920.

Family and domain databases

InterProiView protein in InterPro
IPR013032. EGF-like_CS.
IPR000742. EGF-like_dom.
IPR018711. NAGPA.
PfamiView protein in Pfam
PF09992. NAGPA. 1 hit.
PROSITEiView protein in PROSITE
PS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9UK23-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MATSTGRWLL LRLALFGFLW EASGGLDSGA SRDDDLLLPY PRARARLPRD
60 70 80 90 100
CTRVRAGNRE HESWPPPPAT PGAGGLAVRT FVSHFRDRAV AGHLTRAVEP
110 120 130 140 150
LRTFSVLEPG GPGGCAARRR ATVEETARAA DCRVAQNGGF FRMNSGECLG
160 170 180 190 200
NVVSDERRVS SSGGLQNAQF GIRRDGTLVT GYLSEEEVLD TENPFVQLLS
210 220 230 240 250
GVVWLIRNGS IYINESQATE CDETQETGSF SKFVNVISAR TAIGHDRKGQ
260 270 280 290 300
LVLFHADGQT EQRGINLWEM AEFLLKQDVV NAINLDGGGS ATFVLNGTLA
310 320 330 340 350
SYPSDHCQDN MWRCPRQVST VVCVHEPRCQ PPDCHGHGTC VDGHCQCTGH
360 370 380 390 400
FWRGPGCDEL DCGPSNCSQH GLCTETGCRC DAGWTGSNCS EECPLGWHGP
410 420 430 440 450
GCQRPCKCEH HCPCDPKTGN CSVSRVKQCL QPPEATLRAG ELSFFTRTAW
460 470 480 490 500
LALTLALAFL LLISTAANLS LLLSRAERNR RLHGDYAYHP LQEMNGEPLA
510
AEKEQPGGAH NPFKD
Length:515
Mass (Da):56,073
Last modified:May 18, 2010 - v2
Checksum:i9B80335E7F9DBAA9
GO
Isoform 2 (identifier: Q9UK23-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     392-425: Missing.

Show »
Length:481
Mass (Da):52,368
Checksum:i2FC910C7DB777505
GO
Isoform 3 (identifier: Q9UK23-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     307-309: CQD → WQA
     310-515: Missing.

Show »
Length:309
Mass (Da):33,577
Checksum:i270763749113C946
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti259Q → H in AAF08273 (PubMed:10551838).Curated1
Sequence conflicti405P → R in AAF08273 (PubMed:10551838).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07322584H → Q Rare variant; found in individuals suffering from stuttering; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs755458782Ensembl.1
Natural variantiVAR_073226328R → C Rare variant; found in individuals suffering from stuttering; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs139526942Ensembl.1
Natural variantiVAR_020609465T → I1 PublicationCorresponds to variant dbSNP:rs7188856Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_012267307 – 309CQD → WQA in isoform 3. 1 Publication3
Alternative sequenceiVSP_012268310 – 515Missing in isoform 3. 1 PublicationAdd BLAST206
Alternative sequenceiVSP_012269392 – 425Missing in isoform 2. 1 PublicationAdd BLAST34

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF187072 mRNA. Translation: AAF08273.1.
AK127952 mRNA. Translation: BAG54605.1.
AK314320 mRNA. Translation: BAG36968.1.
AC026458 Genomic DNA. No translation available.
CH471112 Genomic DNA. Translation: EAW85245.1.
BC012194 mRNA. Translation: AAH12194.1.
CCDSiCCDS10527.1. [Q9UK23-1]
RefSeqiNP_057340.2. NM_016256.3. [Q9UK23-1]
UniGeneiHs.21334.

Genome annotation databases

EnsembliENST00000312251; ENSP00000310998; ENSG00000103174. [Q9UK23-1]
ENST00000381955; ENSP00000371381; ENSG00000103174. [Q9UK23-2]
ENST00000562746; ENSP00000455900; ENSG00000103174. [Q9UK23-3]
GeneIDi51172.
KEGGihsa:51172.
UCSCiuc002cyg.4. human. [Q9UK23-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNAGPA_HUMAN
AccessioniPrimary (citable) accession number: Q9UK23
Secondary accession number(s): B2RAS1, Q96EJ8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 21, 2004
Last sequence update: May 18, 2010
Last modified: August 30, 2017
This is version 141 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways