C1QTNF5 explained

Protein Summary

C1q and tumor necrosis factor related protein 5, also known as C1QTNF5, is a protein which in humans is encoded by the C1QTNF5 gene, associated with late-onset retinal degeneration(otherwise known as L-ORD).^{[1] [2]} The C1QTNF5 gene secreted and membrane-linked to a protein which is strongly expressed in retinal pigment epithelium cells.^{[3] [4] [5]}

Function

The CTRP5 protein is a member of the C1q / tumor necrosis factor superfamily, which shows diverse functions including cell adhesion and as components of the basement membrane.^[6]

Clinical significance

A mutation in the C1QTNF5 gene causes late-onset retinal degeneration.More specifically, a single missense mutation (S163R) in the encoded C1QTNF5 protein causes the Late-onset retinal degeneration disease(L-ORD).^[7]

Retinal degeneration is a genetic disorder that originates from the retina, a thin layer located towards the back part of the eye that senses for light.^[1] C1QTNF5 gene associated with L-ORD leads to poor eye sight in dim to dark light which eventually evolves into night blindness known as nyctalopia.

The mutation in the S163R is found in the globular c1q domain.^[8] C1q domain binds to ligands throughout the body that help boost immune responses. The C1q protein can distinguish the different types of potential bacteria and virus ligands that can bind to the C1q domain.^[9] When there is a mutation in the C1q protein the gobular subunits within the C1q that contain binding cites for immune lignands become halted causing L-ORD which can lead to retinal pigment epithelium failure. Retinal pigment epithelium (RPE) helps absorb light through binding to photoreceptors helping to regulate light exposure.^[10]

Origin

S163R mutation in the C1QTNF5 protein is an autosomal dominant disorder that is genetically inherited by one parent being a carrier for the mutation.^[11] Those affected do not begin to see symptoms such as (trouble adjusting to dark or dim areas) until their 40's and early 50's, the reason for the delay in S163 mutation in the C1QTNF5 protein is still unknown, hence the name for the eye disorder Late -onset retinal degeneration beginning in a person's late stages of life.^[1]

Structure

The structure of C1q and Tumor Necrosis Factor Related Protein 5 (C1QTNF5) which is also called CTRP5^[12] has three essential domains. The first domain is a single peptide which is located in N-terminal, the second domain is a collage domain and the third domain is a globular complement 1q (gC1q) that exists in the C-terminal domain.^{[13] [14] [15]} The single mutation S163R is found in the gC1q domain which is the main reason for Late-onset retinal degeneration disease(L-ORD). C1QTNF5 is a part of the C1q family. However, there is a unique feature of the structure of C1QTNF5 that it does not own a Ca 2+ binding site as other members of the C1q family.

Crystal structure

Crystal structure of C1QTNF5 has been taken by Xiongying and Krzysztof and it has two characteristics. One is that the structure of C1QTNF5 seems not to have a Ca 2+ binding site in order to its stability. Also, it is necessary for the function of the members of the C1q family. Another feature is having an unusual sequence which is (F181, F182, G183, G184, W185, P186) that generate a hydrophobic field. In this area, S163 and F182 build H bond, However, the mutation S163 will make a disruption to the H bond.

Further reading

• Shapiro L, Scherer PE . The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor . Current Biology . 8 . 6 . 335–8 . March 1998 . 9512423 . 10.1016/S0960-9822(98)70133-2 . 14287212 . free . 1998CBio....8..335S .
• Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, Sawyer L, Hendry G, Dhillon B, Milam AH, Luthert PJ, Swaroop A, Hastie ND, Jacobson SG, Wright AF . Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration . Human Molecular Genetics . 12 . 20 . 2657–67 . October 2003 . 12944416 . 10.1093/hmg/ddg289 . free .
• Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–24 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
• Ayyagari R, Mandal MN, Karoukis AJ, Chen L, McLaren NC, Lichter M, Wong DT, Hitchcock PF, Caruso RC, Moroi SE, Maumenee IH, Sieving PA . Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation . Investigative Ophthalmology & Visual Science . 46 . 9 . 3363–71 . September 2005 . 16123441 . 10.1167/iovs.05-0159 .
• Subrayan V, Morris B, Armbrecht AM, Wright AF, Dhillon B . Long anterior lens zonules in late-onset retinal degeneration (L-ORD) . American Journal of Ophthalmology . 140 . 6 . 1127–9 . December 2005 . 16376663 . 10.1016/j.ajo.2005.06.023 .
• Foster LJ, Rudich A, Talior I, Patel N, Huang X, Furtado LM, Bilan PJ, Mann M, Klip A . Insulin-dependent interactions of proteins with GLUT4 revealed through stable isotope labeling by amino acids in cell culture (SILAC) . Journal of Proteome Research . 5 . 1 . 64–75 . January 2006 . 16396496 . 10.1021/pr0502626 .
• Shu X, Tulloch B, Lennon A, Vlachantoni D, Zhou X, Hayward C, Wright AF . Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5 . Human Molecular Genetics . 15 . 10 . 1680–9 . May 2006 . 16600989 . 10.1093/hmg/ddl091 . free .
• Book: Shu X, Tulloch B, Lennon A, Hayward C, O'Connell M, Cideciyan AV, Jacobson SG, Wright AF . Biochemical Characterisation of the C1QTNF5 Gene Associated with Late-Onset Retinal Degeneration . Retinal Degenerative Diseases . Advances in Experimental Medicine and Biology . 572 . 41–8 . 2007 . 17249553 . 10.1007/0-387-32442-9_7 . 978-0-387-28464-4 . registration .

Notes and References

1. Lando . Leonardo . Borooah . Shyamanga . 2022-09-30 . Late-Onset Retinal Degeneration: Clinical Perspectives . Clinical Ophthalmology . English . 16 . 3225–3246 . 10.2147/OPTH.S362691 . 9531619 . 36204011 . free .
2. Web site: Entrez Gene: C1QTNF5 C1q and tumor necrosis factor related protein 5.
3. Tu X, Palczewski K . Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration . Journal of Structural Biology . 180 . 3 . 439–46 . December 2012 . 22892318 . 3496058 . 10.1016/j.jsb.2012.07.011 .
4. Stanton CM, Borooah S, Drake C, Marsh JA, Campbell S, Lennon A, Soares DC, Vallabh NA, Sahni J, Cideciyan AV, Dhillon B, Vitart V, Jacobson SG, Wright AF, Hayward C . Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration . Scientific Reports . 7 . 1 . 12147 . September 2017 . 28939808 . 10.1038/s41598-017-11898-3 . 5610255 . 2017NatSR...712147S .
5. Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, Sawyer L, Hendry G, Dhillon B, Milam AH, Luthert PJ, Swaroop A, Hastie ND, Jacobson SG, Wright AF . Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration . Human Molecular Genetics . 12 . 20 . 2657–67 . October 2003 . 12944416 . 10.1093/hmg/ddg289 . free .
6. Shapiro L, Scherer PE . The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor . Current Biology . 8 . 6 . 335–8 . March 1998 . 9512423 . 10.1016/S0960-9822(98)70133-2 . 14287212 . free . 1998CBio....8..335S .
7. Stanton CM, Borooah S, Drake C, Marsh JA, Campbell S, Lennon A, Soares DC, Vallabh NA, Sahni J, Cideciyan AV, Dhillon B, Vitart V, Jacobson SG, Wright AF, Hayward C . Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration . Scientific Reports . 7 . 1 . 12147 . September 2017 . 28939808 . 5610255 . 10.1038/s41598-017-11898-3 . 2017NatSR...712147S .
8. Stanton . Chloe M. . Borooah . Shyamanga . Drake . Camilla . Marsh . Joseph A. . Campbell . Susan . Lennon . Alan . Soares . Dinesh C. . Vallabh . Neeru A. . Sahni . Jayashree . Cideciyan . Artur V. . Dhillon . Baljean . Vitart . Veronique . Jacobson . Samuel G. . Wright . Alan F. . Hayward . Caroline . 2017-09-22 . Novel pathogenic mutations in C1QTNF5 support a dominant negative disease mechanism in late-onset retinal degeneration . Scientific Reports . en . 7 . 1 . 12147 . 10.1038/s41598-017-11898-3 . 2045-2322 . 5610255 . 28939808. 2017NatSR...712147S .
9. Xiong . Xinwei . Li . Chuyi . Zheng . Zhe . Du . Xiaodong . 2021-01-13 . Novel globular C1q domain-containing protein (PmC1qDC-1) participates in shell formation and responses to pathogen-associated molecular patterns stimulation in Pinctada fucata martensii . Scientific Reports . en . 11 . 1 . 1105 . 10.1038/s41598-020-80295-0 . 2045-2322 . 7806589 . 33441832.
10. Yang . Song . Zhou . Jun . Li . Dengwen . 2021-07-28 . Functions and Diseases of the Retinal Pigment Epithelium . Frontiers in Pharmacology . 12 . 727870 . 10.3389/fphar.2021.727870 . 1663-9812 . 8355697 . 34393803 . free .
11. Tu . Xiongying . Palczewski . Krzysztof . April 2014 . The macular degeneration-linked C1QTNF5 (S163) mutation causes higher-order structural rearrangements . Journal of Structural Biology . en . 186 . 1 . 86–94 . 10.1016/j.jsb.2014.02.001 . 3993933 . 24531000.
12. Shu X, Tulloch B, Lennon A, Vlachantoni D, Zhou X, Hayward C, Wright AF . Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5 . Human Molecular Genetics . 15 . 10 . 1680–9 . May 2006 . 16600989 . 10.1093/hmg/ddl091 . free .
13. Mandal MN, Vasireddy V, Reddy GB, Wang X, Moroi SE, Pattnaik BR, Hughes BA, Heckenlively JR, Hitchcock PF, Jablonski MM, Ayyagari R . CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion . Investigative Ophthalmology & Visual Science . 47 . 12 . 5505–13 . December 2006 . 17122142 . 10.1167/iovs.06-0312 .
14. Chavali VR, Khan NW, Cukras CA, Bartsch DU, Jablonski MM, Ayyagari R . A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration . Human Molecular Genetics . 20 . 10 . 2000–14 . May 2011 . 21349921 . 10.1093/hmg/ddr080 . 3080610 .
15. Dinculescu A, Min SH, Dyka FM, Deng WT, Stupay RM, Chiodo V, Smith WC, Hauswirth WW . Pathological Effects of Mutant C1QTNF5 (S163R) Expression in Murine Retinal Pigment Epithelium . Investigative Ophthalmology & Visual Science . 56 . 11 . 6971–80 . October 2015 . 26513502 . 10.1167/iovs.15-17166 . 4627469 .