4b56

Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)

Structural highlights

4b56 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ENPP1_MOUSE Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments.^[1]

Function

ENPP1_MOUSE Appears to modulate insulin sensitivity (By similarity). By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling.^[2] ^[3]

Publication Abstract from PubMed

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative NPP2/autotaxin hydrolyzes lysophospholipids. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a secreted monomer. The structure of secreted NPP1 reveals a characteristic bimetallic active site and a nucleotide-binding groove, but it lacks the lipid-binding pocket and open tunnel present in NPP2. A loop adjacent to the nucleotide-binding site, which is disordered in NPP2, is well ordered in NPP1 and might promote nucleotide binding. Remarkably, the N-terminal somatomedin B-like domains of NPP1, unlike those in NPP2, are flexible and do not contact the catalytic domain. Our results provide a structural basis for the nucleotide pyrophosphatase activity of NPP1 and help to understand how disease-causing mutations may affect NPP1 structure and function.

Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification.,Jansen S, Perrakis A, Ulens C, Winkler C, Andries M, Joosten RP, Van Acker M, Luyten FP, Moolenaar WH, Bollen M Structure. 2012 Oct 2. pii: S0969-2126(12)00330-9. doi:, 10.1016/j.str.2012.09.001. PMID:23041369^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956
↑ Rebbe NF, Tong BD, Finley EM, Hickman S. Identification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5192-6. PMID:1647027
↑ Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956
↑ Jansen S, Perrakis A, Ulens C, Winkler C, Andries M, Joosten RP, Van Acker M, Luyten FP, Moolenaar WH, Bollen M. Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification. Structure. 2012 Oct 2. pii: S0969-2126(12)00330-9. doi:, 10.1016/j.str.2012.09.001. PMID:23041369 doi:http://dx.doi.org/10.1016/j.str.2012.09.001

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OCA

[1] Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956

[2] Rebbe NF, Tong BD, Finley EM, Hickman S. Identification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5192-6. PMID:1647027

[3] Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998 Jul;19(3):271-3. PMID:9662402 doi:http://dx.doi.org/10.1038/956

[4] Jansen S, Perrakis A, Ulens C, Winkler C, Andries M, Joosten RP, Van Acker M, Luyten FP, Moolenaar WH, Bollen M. Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification. Structure. 2012 Oct 2. pii: S0969-2126(12)00330-9. doi:, 10.1016/j.str.2012.09.001. PMID:23041369 doi:http://dx.doi.org/10.1016/j.str.2012.09.001

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4b56

Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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4b56

Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)Structure of ectonucleotide pyrophosphatase-phosphodiesterase-1 (NPP1)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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