# PPIB

## Overview
The PPIB gene encodes the protein peptidylprolyl isomerase B, commonly known as cyclophilin B, which is a member of the cyclophilin family of peptidyl-prolyl cis-trans isomerases. Cyclophilin B is primarily localized in the endoplasmic reticulum and plays a pivotal role in protein folding, particularly in the biosynthesis and processing of collagen. It is a crucial component of the P3H1/CRTAP/PPIB complex, facilitating the proper folding and stability of collagen by catalyzing the cis-trans isomerization of proline residues. This enzymatic activity is essential for the formation of the collagen triple helix, which is vital for the structural integrity of connective tissues. Mutations in the PPIB gene are linked to osteogenesis imperfecta, a genetic disorder characterized by brittle bones, highlighting the clinical significance of cyclophilin B in maintaining bone and skin health (Pyott2011Mutations; van2009PPIB).

## Structure
The PPIB gene encodes cyclophilin B, a peptidyl-prolyl isomerase involved in protein folding. The primary structure of cyclophilin B consists of 208 amino acids, with a signal sequence directing it to the endoplasmic reticulum (ER) (Price1991Human). The secondary structure includes alpha-helices and beta-sheets, forming a characteristic barrel-like fold typical of cyclophilins (Kozlov2010Structural). The tertiary structure of cyclophilin B is defined by its cyclophilin domain, which is crucial for its isomerase activity and binding interactions (Kozlov2010Structural).

Cyclophilin B can form quaternary structures through interactions with other proteins, such as the P3H1/CRTAP complex, which is essential for procollagen folding in the ER (Wu2019Characterization). The protein's surface is involved in binding with other components of this complex, highlighting its role in collagen biosynthesis (Wu2019Characterization). Cyclophilin B also interacts with the P-domain of lectin chaperones like calnexin and calreticulin, independent of its proline isomerization activity (Kozlov2010Structural).

Post-translational modifications, such as glycosylation, may occur, contributing to its functional diversity. Splice variant isoforms of PPIB may exist, further enhancing its functional capabilities (Wu2019Characterization).

## Function
The PPIB gene encodes cyclophilin B (CYPB), a peptidyl-prolyl cis-trans isomerase that plays a crucial role in the biosynthesis and processing of type I procollagen in healthy human cells. CYPB is primarily active in the rough endoplasmic reticulum (RER), where it is involved in the prolyl 3-hydroxylation process and facilitates the folding of proline-rich regions of the C-terminal propeptide. This activity is essential for the proper association of proa chains into trimers, which is critical for the formation of the collagen triple helix structure, ensuring collagen stability and function (Pyott2011Mutations).

CYPB is part of a complex with CRTAP and P3H1, which is responsible for the 3-hydroxylation of proline at position 986 in the a1 chains of collagen type I. This modification is important for proper collagen formation and stability, contributing to the structural integrity of bone and skin (van2009PPIB). In addition to its role in collagen biosynthesis, CYPB also aids in the retention and proper processing of type I procollagen within the RER, preventing its abnormal accumulation and ensuring efficient transport (Pyott2011Mutations).

## Clinical Significance
Mutations in the PPIB gene, which encodes cyclophilin B, are associated with osteogenesis imperfecta (OI), a genetic disorder characterized by fragile bones. These mutations lead to a delay in type I procollagen chain association, resulting in a range of OI phenotypes from perinatal lethal to moderate severity (Pyott2011Mutations). The clinical manifestations of PPIB mutations include severe skeletal deformities, respiratory issues, and in some cases, congenital hearing loss (Caldwell2015Osteogenesis). 

In addition to bone-related symptoms, PPIB mutations have been linked to skin disorders. A missense mutation in the equine PPIB gene is associated with hereditary equine regional dermal asthenia, a condition characterized by skin fragility, suggesting a potential role of PPIB mutations in similar human skin conditions (Tryon2007Homozygosity). 

The absence of cyclophilin B due to PPIB mutations can also affect collagen modification processes, such as lysine hydroxylation, which is crucial for collagen cross-linking and stability. This disruption can lead to impaired mechanical properties of collagen, further contributing to the clinical severity of OI (Terajima2019Cyclophilin).

## Interactions
PPIB, also known as peptidyl-prolyl cis-trans isomerase B, is involved in several protein interactions, particularly within the context of collagen processing. It is a component of the P3H1/CRTAP/PPIB ternary complex, where it plays a crucial role in the folding of collagen type I by facilitating the cis/trans isomerization of X-Pro bonds, essential for the formation of the collagen triple helix (Li2024The). PPIB interacts with the other components of this complex, P3H1 and CRTAP, through specific electrostatic and hydrophobic interactions (Li2024The). The interactions between PPIB and CRTAP are mediated by electrostatic interactions, such as those between E386 CRTAP and K38 PPIB, and D255 CRTAP and K129 PPIB (Li2024The).

PPIB also forms a dual-ternary complex, consisting of two PCP ternary complexes, which assemble asymmetrically. This complex functions as a low-activity reservoir, with PPIB playing a central role in maintaining its structural integrity and enzymatic activity (Li2024The). Pathological mutations in PPIB, such as Gly6Arg and Gly137Asp, significantly impair its ability to form complexes with P3H1 and CRTAP, affecting collagen folding and secretion (Wu2019Characterization). These interactions highlight PPIB's critical role in collagen biosynthesis and its potential implications in collagen-related disorders.


## References


[1. (Tryon2007Homozygosity) Robert C. Tryon, Stephen D. White, and Danika L. Bannasch. Homozygosity mapping approach identifies a missense mutation in equine cyclophilin b (ppib) associated with herda in the american quarter horse. Genomics, 90(1):93–102, July 2007. URL: http://dx.doi.org/10.1016/j.ygeno.2007.03.009, doi:10.1016/j.ygeno.2007.03.009. This article has 94 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ygeno.2007.03.009)

[2. (Caldwell2015Osteogenesis) Kathleen Caldwell, Rose Kreikemeier, Richard Lutz, Paul Esposito, and Eric Rush. Osteogenesis imperfecta caused by ppib mutation with severe phenotype and congenital hearing loss. Journal of Pediatric Genetics, 03(01):029–034, July 2015. URL: http://dx.doi.org/10.3233/PGE-14080, doi:10.3233/pge-14080. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3233/PGE-14080)

[3. (van2009PPIB) Fleur S. van Dijk, Isabel M. Nesbitt, Eline H. Zwikstra, Peter G.J. Nikkels, Sander R. Piersma, Silvina A. Fratantoni, Connie R. Jimenez, Margriet Huizer, Alice C. Morsman, Jan M. Cobben, Mirjam H.H. van Roij, Mariet W. Elting, Jonathan I.M.L. Verbeke, Liliane C.D. Wijnaendts, Nick J. Shaw, Wolfgang Högler, Carole McKeown, Erik A. Sistermans, Ann Dalton, Hanne Meijers-Heijboer, and Gerard Pals. Ppib mutations cause severe osteogenesis imperfecta. The American Journal of Human Genetics, 85(4):521–527, October 2009. URL: http://dx.doi.org/10.1016/j.ajhg.2009.09.001, doi:10.1016/j.ajhg.2009.09.001. This article has 234 citations.](https://doi.org/10.1016/j.ajhg.2009.09.001)

[4. (Kozlov2010Structural) Guennadi Kozlov, Sara Bastos-Aristizabal, Pekka Määttänen, Angelika Rosenauer, Fenglin Zheng, April Killikelly, Jean-François Trempe, David Y. Thomas, and Kalle Gehring. Structural basis of cyclophilin b binding by the calnexin/calreticulin p-domain. Journal of Biological Chemistry, 285(46):35551–35557, November 2010. URL: http://dx.doi.org/10.1074/jbc.m110.160101, doi:10.1074/jbc.m110.160101. This article has 85 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m110.160101)

[5. (Terajima2019Cyclophilin) Masahiko Terajima, Yuki Taga, Wayne A. Cabral, Ying Liu, Masako Nagasawa, Noriko Sumida, Yukako Kayashima, Prashant Chandrasekaran, Lin Han, Nobuyo Maeda, Irina Perdivara, Shunji Hattori, Joan C. Marini, and Mitsuo Yamauchi. Cyclophilin b control of lysine post-translational modifications of skin type i collagen. PLOS Genetics, 15(6):e1008196, June 2019. URL: http://dx.doi.org/10.1371/journal.pgen.1008196, doi:10.1371/journal.pgen.1008196. This article has 21 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1371/journal.pgen.1008196)

[6. (Li2024The) Wenguo Li, Junjiang Peng, Deqiang Yao, Bing Rao, Ying Xia, Qian Wang, Shaobai Li, Mi Cao, Yafeng Shen, Peixiang Ma, Rijing Liao, An Qin, Jie Zhao, and Yu Cao. The structural basis for the collagen processing by human p3h1/crtap/ppib ternary complex. Nature Communications, September 2024. URL: http://dx.doi.org/10.1038/s41467-024-52321-6, doi:10.1038/s41467-024-52321-6. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-024-52321-6)

[7. (Price1991Human) E R Price, L D Zydowsky, M J Jin, C H Baker, F D McKeon, and C T Walsh. Human cyclophilin b: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proceedings of the National Academy of Sciences, 88(5):1903–1907, March 1991. URL: http://dx.doi.org/10.1073/pnas.88.5.1903, doi:10.1073/pnas.88.5.1903. This article has 231 citations.](https://doi.org/10.1073/pnas.88.5.1903)

[8. (Wu2019Characterization) Jiawei Wu, Wenting Zhang, Li Xia, Lingling Feng, Zimei Shu, Jing Zhang, Wei Ye, Naiyan Zeng, and Aiwu Zhou. Characterization of ppib interaction in the p3h1 ternary complex and implications for its pathological mutations. Cellular and Molecular Life Sciences, 76(19):3899–3914, April 2019. URL: http://dx.doi.org/10.1007/s00018-019-03102-8, doi:10.1007/s00018-019-03102-8. This article has 10 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-019-03102-8)

[9. (Pyott2011Mutations) Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human Molecular Genetics, 20(8):1595–1609, January 2011. URL: http://dx.doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 109 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddr037)