The Polybasic Insertion in Autotaxin α Confers Specific Binding to Heparin and Cell Surface Heparan Sulfate Proteoglycans

Houben, Anna J.S.; Wijk, Xander M R van; Meeteren, Laurens A. van; Zeijl, Leonie van; Westerlo, Els M.A. van de; Hausmann, Jens; Fish, Alexander; Perrakis, Anastassis; Kuppevelt, Toin H. Van; Moolenaar, Wouter H.

doi:10.1074/jbc.m112.358416

Cited by 54 publications

(49 citation statements)

References 49 publications

(57 reference statements)

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“…All ATX isoforms display similar lysoPLD activities and substrate preferences ( 55,56,59 ). ATX-catalyzed substrate hydrolysis follows simple Michaelis-Menten kinetics, with no evidence for an interfacial activation mechanism and consistent with the notion that ATX acts on free lysophospholipids in the aqueous phase.…”

Section: Atx Structure-functionsupporting

confidence: 62%

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Autotaxin: structure-function and signaling

Perrakis

Moolenaar

2014

Journal of Lipid Research

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148

127

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Section: Atx Structure-functionsupporting

confidence: 62%

“…most likely through the Arg/Lys-rich clusters in the insertion, whereas ATX ␤ does not ( 59 ). Heparin enhanced the lysoPLD activity of ATX ␣ toward LPC up to 2-fold, but it had no detectable effect on the activity of ATX ␤ ( 59 ).…”

Section: Lpa Production and Bioavailabilitymentioning

confidence: 99%

Autotaxin: structure-function and signaling

Perrakis

Moolenaar

2014

Journal of Lipid Research

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148

127

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“…The slow release of LPA, taking place in the range of tens of seconds 28 , suggested a mechanism where ATX could also act as an LPA carrier, spreading LPA signal to distal locations from those where LPC was taken. Such a model is also supported by data that show that Autotaxin can be recruited to the cell surface binding both to integrins 13,31 and surface heparin sulfate proteoglycans 32 .…”

Section: Fluorescent Probe 12-(n-methyl-n-(7-nitrobenz-2-oxa-13-diazmentioning

confidence: 65%

“…Second, it has been shown that ATX binds surface integrins through the SMB domains 13,31,38 , whereas the longer isoform of ATX (ATXα) binds to heparan sulfate proteoglycans 32 . While this binding will localize ATX at the cell surface, likely making LPA delivery to surface receptors more efficient, it cannot be excluded that it also affects the kinetics of LPC hydrolysis in our model.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency

Salgado-Polo

Fish

Matsoukas

et al. 2018

Preprint

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Autotaxin is a secreted phosphodiesterase that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key cellular responses such as migration, proliferation and survival, implicating ATX-LPA signalling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, the "pocket" and the "tunnel". Here, we revisit the kinetics of the ATX catalytic cycle in light of allosteric regulation, dissecting the different steps and pathways that lead to LPC hydrolysis. Consolidating all experimental kinetics data to a comprehensive catalytic model supported by molecular modelling simulations, suggests a positive feedback mechanism, regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend current understanding of ATX hydrolysis in light of the allosteric regulation by produced LPA species, and have implications for the design and application of orthosteric and allosteric ATX inhibitors.

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“…Although no specifi c differences in the core mechanism of catalysis or physiological activities between the fi ve ATX variants have yet been reported, differences in enzymatic parameters, tissue expression levels, and isoform stability have been documented ( 7 ). For instance, ATX ␤ is the most abundant isoform found in plasma ( 10 ), whereas ATX ␣ is unstable and less common in peripheral tissues due to a long polybasic cleavable insert that mediates ATX recruitment to the cell membrane through the interaction with heparan sulfate proteoglycans ( 7,11 ). The identity and functional signifi cance of factors regulating alternative splicing of exons 12 and 21, as well as the deletion of the VEPK peptide in the lasso loop, remain to be determined.…”

Section: Structure and Enzymatic Activitymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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The Polybasic Insertion in Autotaxin α Confers Specific Binding to Heparin and Cell Surface Heparan Sulfate Proteoglycans

Cited by 54 publications

References 49 publications

Autotaxin: structure-function and signaling

Autotaxin: structure-function and signaling

Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

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