Ferritin light chain

Ferritin light chain is a protein that in humans is encoded by the FTL gene.{{cite journal | vauthors = Lebo RV, Kan YW, Cheung MC, Jain SK, Drysdale J | title = Human ferritin light chain gene sequences mapped to several sorted chromosomes | journal = Hum. Genet. | volume = 71 | issue = 4 | pages = 325–8 | date = December 1985 | pmid = 3000916 | doi = 10.1007/BF00388458 | s2cid = 2574558 }}{{cite journal | vauthors = Gasparini P, Calvano S, Memeo E, Bisceglia L, Zelante L | title = Assignment of ferritin L gene (FTL) to human chromosome band 19q13.3 by in situ hybridization | journal = Ann. Genet. | volume = 40 | issue = 4 | pages = 227–8 | date = Apr 1997 | pmid = 9526618 }}{{cite web |title=FTL ferritin, light polypeptide |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2512 |publisher=National Center for Biotechnology Information |date=5 July 2009 |access-date=20 July 2009}} Ferritin is the major protein responsible for storing intracellular iron in prokaryotes and eukaryotes. It is a heteropolymer consisting of 24 subunits, heavy and light ferritin chains. This gene has multiple pseudogenes.

It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these assisted reproductive technologies.{{cite journal | vauthors = Zhang Y, Zhang YL, Feng C, Wu YT, Liu AX, Sheng JZ, Cai J, Huang HF | title = Comparative proteomic analysis of human placenta derived from assisted reproductive technology | journal = Proteomics | volume = 8 | issue = 20 | pages = 4344–56 | date = October 2008 | pmid = 18792929 | doi = 10.1002/pmic.200800294 | s2cid = 206362532 }}

Function

Iron is extremely important in the development of neurons, transport through iron-sulfur clusters, the electron transport chain, and synthesis and breakdown of neurotransmitters. The function of the FTL is to act as both an iron reservoir and to remove excess iron from the body. Since iron plays a role in electron transfer, there is potential for the generation of free, highly toxic radicals which makes the role of the FTL as an iron detoxifier very significant.{{Cite journal|last1=Vidal|first1=Ruben|last2=Miravalle|first2=Leticia|last3=Gao|first3=Xiaoying|last4=Barbeito|first4=Ana G.|last5=Baraibar|first5=Martin A.|last6=Hekmatyar|first6=Shahryar K.|last7=Widel|first7=Mario|last8=Bansal|first8=Navin|last9=Delisle|first9=Marie B.|last10=Ghetti|first10=Bernardino|date=2008-01-02|title=Expression of a Mutant Form of the Ferritin Light Chain Gene Induces Neurodegeneration and Iron Overload in Transgenic Mice|journal=The Journal of Neuroscience|volume=28|issue=1|pages=60–67|doi=10.1523/JNEUROSCI.3962-07.2008|issn=0270-6474|pmc=2394191|pmid=18171923}} The rates of iron uptake and release may be affected by changes to the components of the ferritin light chains and heavy chains. Although the ferritin light chain unlike the ferritin heavy chain has no ferroxidase activity, the light chain may be responsible for the electron transfer across the ferritin protein cage.{{cite journal | vauthors = Carmona U, Li L, Zhang L, Knez M | title = Ferritin light-chain subunits: key elements for the electron transfer across the protein cage | journal = Chemical Communications | volume = 50 | issue = 97 | pages = 15358–15361 | year = 2014 | pmid = 25348725 | doi = 10.1039/c4cc07996e }}

Clinical significance

Oxidative stress caused by iron radicals generated in the ETC and an increase in iron levels caused by defects in the FTL gene has been known to be a cause of the onset of neurodegenerative diseases and hyperferritinemia-cataract syndrome.{{cite journal | vauthors = Zandman-Goddard G, Shoenfeld Y | title = Ferritin in autoimmune diseases | journal = Autoimmun Rev | volume = 6 | issue = 7 | pages = 457–63 | year = 2007 | pmid = 17643933 | doi = 10.1016/j.autrev.2007.01.016 }}

Mutations of the FTL gene cause the rare adult-onset basal ganglia disease also known as neuroferritinopathy.{{cite journal | vauthors = Gregory A, Hayflick SJ | title = Genetics of neurodegeneration with brain iron accumulation | journal = Curr Neurol Neurosci Rep | volume = 11 | issue = 3 | pages = 254–61 | year = 2011 | pmid = 21286947 | doi = 10.1007/s11910-011-0181-3 | pmc = 5908240 }} These mutations are specifically in exon four of the FTL gene. There are two distinct toxic mechanisms that lead to neuroferritinopathy and these are abnormalities in iron metabolism and the creation of free iron radicals, resulting in oxidative stress and cell death.{{Cite journal|last1=Nishida|first1=Katsuya|last2=Garringer|first2=Holly|last3=Futamura|first3=Naonobu|last4=Funakawa|first4=Itara|last5=Jinnai|first5=Kenji|last6=Vidal|first6=Ruben|last7=Takao|first7=Masaki|date=12 April 2014|title=A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation|journal=Journal of the Neurological Sciences|volume=342|issue=1–2|pages=173–177|doi=10.1016/j.jns.2014.03.060|pmid=24825732|pmc=4048789|via=Hunter College Libraries}}

Interactions

Ferritin light chain has been shown to interact with FTH1.{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}{{cite journal | vauthors = Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–68 | date = Sep 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 | hdl = 11858/00-001M-0000-0010-8592-0 | s2cid = 8235923 | hdl-access = free }} An oxygen molecule acts as the terminal electron acceptor during the oxidation of iron in aerobic metabolism. A study conducted with different apoferritins with distinct compositions of heavy and light subunits revealed that both subunits have key roles in the electron transport chain. Neither subunit on its own has the ability to reduce cytochrome c and thus the first step, the oxidation of Fe²⁺ to Fe³⁺, can be carried out by the heavy chain and the light chains are responsible for the transfer of electrons.

FTL is regulated by iron and with an increase in iron, there is both an increase in the FTL expression and PEN-2 levels, which results in increased γ- secretase activity. In relation to this, the downregulation of FTL expression leads to a decrease in the protein levels of PEN-2.{{Cite journal|last1=Li|first1=Xinxin|last2=Liu|first2=Yiqian|last3=Zheng|first3=Qiuyang|last4=Yao|first4=Guorui|last5=Cheng|first5=Peng|last6=Bu|first6=Guojun|last7=Xu|first7=Huaxi|last8=Zhang|first8=Yun-Wu|date=8 May 2013|title=Ferritin light chain interacts with PEN-2 and affects gamma- secretase activity|journal= Neuroscience Letters|volume=548|pages=90–94|doi=10.1016/j.neulet.2013.05.018|pmid=23685131|pmc=3724929}}

References

External links

[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=neuroferritin GeneReviews/NCBI/NIH/UW entry on Neuroferritinopathy]