Journal article
Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2
The Journal of biological chemistry, v 279(43), pp 44987-44995
22 Oct 2004
PMID: 15316017
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Inositol-5-phosphatases are important enzymes involved in the regulation of diverse cellular processes from synaptic vesicle recycling to insulin signaling. We describe a comparative study of two representative inositol-5-phosphatases, Schizosaccharomyces pombe synaptojanin (SPsynaptojanin) and human SH2 domain- containing inositol-5-phosphatase SHIP2. We show that in addition to Mg super(2+), transition metals such as Mn super(2+), Co super(2+), and Ni super(2+) are also effective activators of SPsynaptojanin. In contrast, Ca super(2+) and Cu super(2+) are inhibitory. We provide evidence that Mg super(2+) binds the same site occupied by Ca super(2+) observed in the crystal structure of SPsynaptojanin complexed with inositol 1,4- bisphosphate (Ins(1,4)P sub(2)). Ionizations important for substrate binding and catalysis are defined for the SPsynaptojanin-catalyzed Ins(1,4,5)P sub(3) reaction. Kinetic analysis with four phosphatidylinositol lipids bearing a 5- phosphate and 54 water-soluble inositol phosphates reveals that SP-synaptojanin and SHIP2 possess much broader substrate specificity than previously appreciated. The rank order for SPsynaptojanin is Ins(2,4,5)P sub(3) > phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P sub(2)) ~ Ins(4,5)P sub(2) ~ Ins(1,4,5)P sub(3) ~ Ins(4,5,6)P sub(3) > PtdIns(3,5)P sub(2) ~ PtdIns(3,4,5)P sub(3) ~ Ins(1,2,4,5)P sub(4) ~ Ins(1,3,4,5)P sub(4) ~ Ins-(2,4,5,6)P sub(4) ~ Ins(1,2,4,5,6)P sub(5). The rank order for SHIP2 is Ins(1,2,3,4,5)P sub(5) > Ins(1,3,4,5)P sub(4) > PtdIns(3,4,5)P sub(4) ~ PtdIns(3,5)P sub(2) ~ Ins(1,4,5,6)P sub(4) ~ Ins(2,4,5,6)P sub(4). Because inositol phosphate isomers elicit different biological activities, the extended substrate specificity for SPsynaptojanin and SHIP2 suggest that these enzymes likely have multiple roles in cell signaling and may regulate distinct pathways. The unique substrate specificity profiles and the importance of 2-position phosphate in binding also have important implications for the design of potent and selective SPsynaptojanin and SHIP2 inhibitors for pharmacological investigation.
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Details
- Title
- Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2
- Creators
- Yuling Chi - Albert Einstein College of MedicineBo Zhou - Yeshiva UniversityWei-Qing Wang - Yeshiva UniversitySung-Kee ChungYong-Uk KwonYoung-Hoon AhnYoung-Tae ChangYosuke Tsujishita - United States Department of Health and Human ServicesJames Hurley - United States Department of Health and Human ServicesZhong-Yin Zhang - Yeshiva University
- Publication Details
- The Journal of biological chemistry, v 279(43), pp 44987-44995
- Publisher
- ASBMB Publications / Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000224505600090
- Scopus ID
- 2-s2.0-7244226331
- Other Identifier
- 991020100080804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology