関: peptidylprolyl isomerase、PPIase

WordNet

an enzyme that catalyzes its substrate to an isomeric form

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/13 04:28:56」(JST)

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Prolyl isomerase (also known as peptidylprolyl isomerase or PPIase) is an enzyme (EC 5.2.1.8) found in both prokaryotes and eukaryotes that interconverts the cis and trans isomers of peptide bonds with the amino acid proline.^[1] Proline has an unusually conformationally restrained peptide bond due to its cyclic structure with its side chain bonded to its secondary amine nitrogen. Most amino acids have a strong energetic preference for the trans peptide bond conformation due to steric hindrance, but proline's unusual structure stabilizes the cis form so that both isomers are populated under biologically relevant conditions. Proteins with prolyl isomerase activity include cyclophilin, FKBPs, and parvulin, although larger proteins can also contain prolyl isomerase domains.

Protein folding

Proline is unique among the natural amino acids in having a relatively small difference in free energy between the cis configuration of its peptide bond and the more common trans form. The activation energy required to catalyse the isomerisation between cis and trans is relatively high: ~20kcal/mol (c.f. ~0kcal/mol for regular peptide bonds). Unlike regular peptide bonds, the X-prolyl peptide bond will not adopt the intended conformation spontaneously, thus, the process of cis-trans isomerization can be the rate-limiting step in the process of protein folding. Prolyl isomerases therefore function as protein folding chaperones. Cis peptide bonds N-terminal to proline residues are often located at the first residue of certain types of tight turns in the protein backbone. Proteins that contain structural cis-prolines in the native state include ribonuclease A, ribonuclease T1, beta lactamase, cyclophilin, and some interleukins.

Prolyl isomerase folding can be autocatalytic and therefore the speed of folding depends on reactant concentration. Parvulin and human cytosolic FKBP are thought to catalyze their own folding processes.

Evidence for proline isomerization

Methods for identifying the presence of a rate-limiting proline isomerization process in a protein folding event include:

Activation energies consistent with proline isomerization, which typically has an activation of about 20 kcal/mol.
Two-state folding kinetics indicative of both fast-folding and slow-folding populations in the unfolded or denatured state.
"Double-jump" assays in which proline-containing proteins are unfolded and refolded, and the population of non-native proline conformations are studied as a function of the extent of folding.
Acceleration of the in vitro folding rate by the addition of a prolyl isomerase.
Acceleration of the in vitro folding rate in mutant protein variants with one or more proline residues replaced by another amino acid.

It is important to note that not every proline peptide bond is critical to the structure or function of a protein, and not every such bond has a significant influence on folding kinetics, especially trans bonds. Furthermore, some prolyl isomerases have a degree of sequence specificity and therefore may not catalyze the isomerization of prolines in certain sequence contexts.

Assays for prolyl isomerase activity

Prolyl isomerase activity was first discovered using a chymotrypsin-based assay. The proteolytic enzyme chymotrypsin has a very high substrate specificity for the four-residue peptide Ala-Ala-Pro-Phe only when the proline peptide bond is in the trans state. Adding chymotrypsin to a solution containing a reporter peptide with this sequence results in the rapid cleavage of about 90% of the peptides, while those peptides with cis proline bonds - about 10% in aqueous solution - are cleaved at a rate limited by uncatalyzed proline isomerization. The addition of a potential prolyl isomerase will accelerate this latter reaction phase if it has true prolyl isomerase activity.

References

^ Fischer G, Schmid FX (1990). "The mechanism of protein folding. Implications of in vitro refolding models for de novo protein folding and translocation in the cell". Biochemistry 29 (9): 2205–2212. doi:10.1021/bi00461a001. PMID 2186809.

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English Journal

Cyclophilin A is a new M cell marker of bovine intestinal epithelium.

Hondo T1, Someya S1, Nagasawa Y1, Terada S1, Watanabe H1,2, Chen X1, Watanabe K1, Ohwada S1, Kitazawa H3, Rose MT4, Nochi T1, Aso H5.
Cell and tissue research.Cell Tissue Res.2016 Jun;364(3):585-97. doi: 10.1007/s00441-015-2342-1. Epub 2016 Feb 22.
Microfold (M) cells in the follicle-associated epithelium (FAE) of Peyer's patches contribute to the mucosal immune response by the transcytosis of microorganisms. The mechanism by which M cells take up microorganisms, and the functional proteins by which they do this, are not clear. In order to exp
PMID 26899250

Determining the roles of a conserved tyrosine residue in a Mip-like peptidyl-prolyl cis-trans isomerase.

Polley S1, Chakravarty D1, Chakrabarti G2, Sau S3.
International journal of biological macromolecules.Int J Biol Macromol.2016 Jun;87:273-80. doi: 10.1016/j.ijbiomac.2016.02.070. Epub 2016 Mar 2.
The FKBP22 and the related peptidyl-prolyl cis-trans isomerases dimerize using their N-terminal domains. Conversely, their C-terminal domains possess both the substrate and inhibitor binding sites. To delineate the roles of a conserved Tyr residue at their N-terminal domains, we have studied a FKBP2
PMID 26944658

Protein interacting with NIMA (never in mitosis A)-1 regulates axonal growth cone adhesion and spreading through myristoylated alanine-rich C kinase substrate isomerization.

Sosa LJ1, Malter JS2, Hu J2, Bustos Plonka F3, Oksdath M3, Nieto Guil AF3, Quiroga S3, Pfenninger KH1.
Journal of neurochemistry.J Neurochem.2016 Jun;137(5):744-55. doi: 10.1111/jnc.13612. Epub 2016 Apr 8.
Axonal growth cone motility requires precise regulation of adhesion to navigate the complex environment of the nervous system and reach its target. Myristoylated alanine-rich C kinase substrate (MARCKS) protein is enriched in the developing brain and plays an important, phosphorylation-dependent rol
PMID 26991250

Japanese Journal

Peptidyl–Prolyl cis/trans Isomerase NIMA-Interacting 1 as a Therapeutic Target in Hepatocellular Carcinoma

Kim Garam,Kim Jin Young,Choi Hong Seok
Biological and Pharmaceutical Bulletin 38(7), 975-979, 2015
… The recent identification and characterization of the enzyme peptidyl–prolyl cis/trans isomerase never in mitosis A (NIMA)-interacting 1 (PIN1) has led to the discovery of a new mechanism regulating phosphorylation in cell signaling. …
NAID 130005086285

2P023 Pin1のプロリン異性化活性とタウタンパク質に対する凝集抑制活性との関係(01B. 蛋白質:構造機能相関,ポスター,第52回日本生物物理学会年会(2014年度))

Ikura Teikichi,Ito Nobutoshi
生物物理 54(SUPPLEMENT_1-2), S198, 2014-08-20
NAID 110009932569

Involvement of peptidyl-prolyl isomerase Pin1 in the inhibitory effect of fluvastatin on endothelin-1-induced cardiomyocyte hypertrophy

Sakai Satoshi,Shimojo Nobutake,Kimura Taizo,Tajiri Kazuko,Maruyama Hidekazu,Homma Satoshi,Kuga Keisuke,Mizutani Taro,Aonuma Kazutaka,Miyauchi Takashi
Life sciences 102(2), 98-104, 2014-05
AimsCardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit …
NAID 120005456068

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リンク元	「プロリルイソメラーゼ」「PPIase」
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「プロリルイソメラーゼ」

Peptidyl-prolyl cis-trans isomerase, PpiC-type
Identifiers
Symbol	PPIase_PpiC
Pfam	PF00639
InterPro	IPR000297
PROSITE	PDOC00840
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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PMC	articles
PubMed	articles
NCBI	proteins

Peptidylprolyl isomerase
Identifiers
EC number	5.2.1.8
CAS number	95076-93-0
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins