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2  structures 2057  species 0  interactions 2673  sequences 27  architectures

Family: Rotamase_2 (PF13145)

Summary: PPIC-type PPIASE domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Prolyl isomerase". More...

Prolyl isomerase Edit Wikipedia article

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
Peptidyl-prolyl cis-trans isomerase, PpiC-type
PDB 1nmw EBI.jpg
Identifiers
Symbol PPIase_PpiC
Pfam PF00639
InterPro IPR000297
PROSITE PDOC00840

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[edit]

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, 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[edit]

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

  1. Activation energies consistent with proline isomerization, which typically has an activation of about 20 kcal/mol.
  2. Two-state folding kinetics indicative of both fast-folding and slow-folding populations in the unfolded or denatured state.
  3. "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.
  4. Acceleration of the in vitro folding rate by the addition of a prolyl isomerase.
  5. 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[edit]

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[edit]

  1. ^ 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. 

Further reading[edit]

  • Balbach J, Schmid FX (2000). "Proline isomerizarion and its catalysis in protein folding". In Pain RH. Mechanisms of protein folding (2nd ed.). Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-963788-1. 
  • Fischer G, Bang H, Mech C (1984). "[Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides]". Biomed. Biochim. Acta (in German) 43 (10): 1101–11. PMID 6395866. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

PPIC-type PPIASE domain Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan FKBP (CL0487), which has the following description:

This superfamily includes the FKBP domain which catalyses the peptidyl-prolyl cis-trans isomerisation reaction. The superfamily also includes the C-terminal domain of GreA and the c-terminal dmoain of 3-mercaptopyruvate sulfurtransferase.

The clan contains the following 5 members:

DUF1930 GreA_GreB Rotamase Rotamase_2 Rotamase_3

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(206)
Full
(2673)
Representative proteomes NCBI
(6738)
Meta
(2215)
RP15
(194)
RP35
(373)
RP55
(478)
RP75
(569)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(206)
Full
(2673)
Representative proteomes NCBI
(6738)
Meta
(2215)
RP15
(194)
RP35
(373)
RP55
(478)
RP75
(569)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(206)
Full
(2673)
Representative proteomes NCBI
(6738)
Meta
(2215)
RP15
(194)
RP35
(373)
RP55
(478)
RP75
(569)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Jackhmmer:O25628
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 206
Number in full: 2673
Average length of the domain: 123.40 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 28.69 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.0 27.0
Noise cut-off 26.9 26.9
Model length: 121
Family (HMM) version: 1
Download: download the raw HMM for this family

Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Rotamase_2 domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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