Crystal Structure of the Catalytic Fragment of Human Brain 2′,3′-Cyclic-nucleotide 3′-Phosphodiesterase

Sakamoto, Yasumitsu; Tanaka, Nobutada; Ichimiya, Tomomi; Kurihara, Tadashi; Nakamura, Kazuo

doi:10.1016/j.jmb.2004.12.024

Cited by 42 publications

(56 citation statements)

References 37 publications

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“…X-ray and NMR structures of the catalytic fragment (CF) highlighted a bilobar fold composed of two repeated a + b modules related by pseudotwofold symmetry (Kozlov et al 2003;Sakamoto et al 2005). The two HxT motifs are located at the active site.…”

Section: Resultsmentioning

confidence: 99%

Mammalian 2′,3′ cyclic nucleotide phosphodiesterase (CNP) can function as a tRNA splicing enzyme in vivo

Schwer¹,

Aronova²,

Ramı́rez³

et al. 2007

RNA

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Yeast and plant tRNA splicing entails discrete healing and sealing steps catalyzed by a tRNA ligase that converts the 29,39 cyclic phosphate and 59-OH termini of the broken tRNA exons to 39-OH/29-PO 4 and 59-PO 4 ends, respectively, then joins the ends to yield a 29-PO 4 , 39-59 phosphodiester splice junction. The junction 29-PO 4 is removed by a tRNA phosphotransferase, Tpt1. Animal cells have two potential tRNA repair pathways: a yeast-like system plus a distinctive mechanism, also present in archaea, in which the 29,39 cyclic phosphate and 59-OH termini are ligated directly. Here we report that a mammalian 29,39 cyclic nucleotide phosphodiesterase (CNP) can perform the essential 39 end-healing steps of tRNA splicing in yeast and thereby complement growth of strains bearing lethal or temperature-sensitive mutations in the tRNA ligase 39 end-healing domain. Although this is the first evidence of an RNA processing function in vivo for the mammalian CNP protein, it seems unlikely that the yeast-like pathway is responsible for animal tRNA splicing, insofar as neither CNP nor Tpt1 is essential in mice.

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Section: Resultsmentioning

confidence: 99%

Mammalian 2′,3′ cyclic nucleotide phosphodiesterase (CNP) can function as a tRNA splicing enzyme in vivo

Schwer¹,

Aronova²,

Ramı́rez³

et al. 2007

RNA

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“…The WB indicated that both M125-D1 ( Figure 4A) and M125-D2 ( Figure 4B) were reactive to denatured (bovine) CNPase, denatured hGFAP and denatured hMBP, but not to denatured hMOG. The polyreactivity of M125-D to CNPase, MBP, and GFAP in WB cannot be explained by similarities of these proteins to CNPase with regard to sequence, structure or isoelectric point (pI) (Sakamoto et al, 2005). Purified antigens used in this study were also not contaminated with other myelin components since the GFAP protein was free of MBP (and vice versa) when we tested them with the respective commercially available anti-MBP and anti-GFAP antibodies (data not shown).…”

Section: Polyreactivity Of M125-dmentioning

confidence: 88%

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

Lambracht-Washington

O’Connor

Cameron

et al. 2007

Journal of Neuroimmunology

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We re-engineered the immunoglobulin rearrangements from clonally expanded CSF B cells of three Multiple Sclerosis patients as Fab fragments, and used three methods to test for their Ag-specificity. Nine out of ten Fab fragments were reactive to Myelin Basic Protein (MBP). The one Fab that did not react to MBP was a product of receptor editing. Two of the nine MBP-reactive Fabs were also reactive to GFAP and CNPase, indicating that these clones were polyreactive. Targeting the mechanisms that allows these self-reactive B cells to reside in the CSF of MS patients may prove to be a potent immunotherapeutic strategy.

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“…Sakamoto et al postulated a putative binding mode and active site for the enzyme, when they solved the fi rst CNPase crystal structure [66] . A simple mechanistic reaction scheme for CNPase could be then described.…”

Section: Activitymentioning

confidence: 99%

Section: Activitymentioning

confidence: 99%

“…Both the NMR and the crystal structure showed the catalytic domain to share high structural homology with 2H phosphoesterases, with a pseudo 2-fold symmetric double His-X-Thr-X motif in the active site (Fig. 3A, B) [28,29,66] .Since its initial structural characterization, CNPase has been extensively studied, and a detailed mechanistic reaction scheme has recently been described, based on protein-ligand complex structures (Fig. 3C, D) [30,67] .…”

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confidence: 99%

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The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Raasakka

Kursula

2014

Neurosci. Bull.

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The membrane-anchored myelin enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological signifi cance of CNPase, providing ideas and directions for future research.Keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; calmodulin; central nervous system; cytoskeleton; myelin proteins; RNA ·Review· IntroductionMyelin is a specialized multilamellar structure, which is wrapped around neuronal axons by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .Several myelin proteins have delicately regulated expression levels and functions. Past research using cell culture and animal models have outlined the importance of various proteins in demyelination -a situation where myelin undergoes morphological changes and loss [6] .Demyelination causes neurological disorders, including multiple sclerosis (MS), Charcot-Marie-Tooth disease, and leukodystrophies, such as Pelizaeus-Merzbacher disease [7][8][9][10] .2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)is one of the most abundant proteins in CNS myelin and a possible auto-antigen in MS [4,11] . The high expression levels of CNPase, together with its rather unusual enzymatic after the initial di...

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Crystal Structure of the Catalytic Fragment of Human Brain 2′,3′-Cyclic-nucleotide 3′-Phosphodiesterase

Cited by 42 publications

References 37 publications

Mammalian 2′,3′ cyclic nucleotide phosphodiesterase (CNP) can function as a tRNA splicing enzyme in vivo

Mammalian 2′,3′ cyclic nucleotide phosphodiesterase (CNP) can function as a tRNA splicing enzyme in vivo

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

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