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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.

English Journal

Pin1 and secondary hyperparathyroidism of chronic kidney disease: gene polymorphisms and protein levels.

Zhao Y1, Zhang LL2, Ding FX2, Cao P2, Qi YY2, Wang J2.
Renal failure.Ren Fail.2017 Nov;39(1):159-165. doi: 10.1080/0886022X.2016.1256310. Epub 2016 Nov 23.
PMID 27876426

Conformational dynamics of Peb4 exhibit "mother's arms" chain model: a molecular dynamics study.

Dantu SC1, Khavnekar S2, Kale A2.
Journal of biomolecular structure & dynamics.J Biomol Struct Dyn.2017 Aug;35(10):2186-2196. doi: 10.1080/07391102.2016.1209131. Epub 2016 Jul 19.
PMID 27434141

Cross-Platform Comparison of Computer-assisted Image Analysis Quantification of In Situ mRNA Hybridization in Investigative Pathology.

Holzer TR1, Hanson JC, Wray EM, Bailey JA, Kennedy KR, Finnegan PR, Nasir A, Credille KM.
Applied immunohistochemistry & molecular morphology : AIMM.Appl Immunohistochem Mol Morphol.2017 Jul 4. doi: 10.1097/PAI.0000000000000542. [Epub ahead of print]
PMID 28682833

Japanese Journal

2Gp11 分子シャペロンPPIaseとの融合化による芳香族アミノ酸デカルボキシラーゼの可溶性向上(代謝工学/脂質工学,一般講演)

小柳喬,原彩由美,南博道,片山高嶺,熊谷英彦,三沢典彦
日本生物工学会大会講演要旨集 64, 64, 2012-09-25
NAID 110009609484

2Cp08 Thermococcus kodakarensis由来高分子量型及び低分子量型FKBPの構造機能解析(酵素学,酵素工学,一般講演)

安東洋平,ブディマンチャヒョウ,古賀雄一,金谷茂則
日本生物工学会大会講演要旨集 64, 40, 2012-09-25
NAID 110009609399

2S4a03 基質親和性が広い海洋細菌由来オキシゲナーゼを用いた芳香族化合物のバイオコンバージョン(海洋資源発掘のバイオテクノロジー最前線,ワークショップ)

三沢典彦,音松俊彦
日本生物工学会大会講演要旨集 63, 97, 2011-08-25
NAID 110008911219

「peptidylprolyl isomerase」

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