https://pubmed.ncbi.nlm.nih.gov/?term=Kelch+proteins+and+Sceletal+muscle+
tÄSSÄ YLLÄOLEVASSA LINKISSÄ ON 81 ARTIKKELIA JOTKA TULIVAT ESIIN pUBmED HAKULAITTEELLA HAKU: KELC REPEAT PROTEINS AND SCELETAL MUSCLE.
Hyvä taulukko näsitä ihmisen lihassairauksia, myopatiaa ja syöpää aiheuttavista Kelch proteiinitaudeista on vuoden 2014 artikkelissa . Tässä mainitaan 63 kelch toiston omaavaa proteiinia.
Kelch proteins: emerging roles in skeletal muscle development and diseases.
Gupta VA, Beggs AH. Skelet Muscle. 2014 Jun 1;4:11. doi: 10.1186/2044-5040-4-11. eCollection 2014. PMID: 24959344 Free PMC article. Review.
Yleistietoa Kelch - toiston omaavista proteeineista saa sekä GeneCards tietä hakemalla yhden toisensa jälkeen tai koko ryhmää käsitelevistä artikkelistä. Päivitän ryhmätietoja tähän, sillä katsoin ne ennen pandemiaa ja siten tuli tuo koronavirus viemään lukuintressit ja nyt vasta päivitän 2023 kelchit vaikka uuttera Sars-Cov-2 kyllä piti huolta että niitäkin kuului interaktioproteiinien joukkoon.
Tällä kertaa päivityksen indisoi neuromuskulaariset taudit joitten ryhmiä nyt katson. Vaikuttaa että ataxiinien puolellakin on näitä propellisia molekyylejä. Aktsotaan kerään myös niitten luettelon pian.
GUPTAn artikkelin antamaa pöerustietoa ryhmästä:
https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-4-11/figures/1
The Kelch Superfamily. ( KELCH superperheen perusjakoa ja domeenijärjestelmää).
(A) The Kelch family consists of 63 proteins that are subclassified in to KLHL, KBTBD and KLHDC subfamilies.
(B) Structure of Kelch domain of rat KLHL41 (PDB code 2WOZ) comprising six repeats that form the complete Kelch domain. The structure was generated using PyMOL (http://www.pymol.org).
(C) Prototype members of different subfamilies showing different domain organization.
KLHL proteins have an N-terminal BTB/POZ, a BACK and C-terminal Kelch repeats.
KBTBD proteins contain an N-terminal BTB domain and Kelch repeats. The BACK domain is normally absent in KBTBD proteins.
KLHDC proteins lack both BTB/POZ and BACK domains and contain either Kelch repeats alone or with other domains such as transmembrane (for example, KLHDC7A), Glycine rich (for example, KLHDC10), or Lish and CTLH domains (for example, MKLN1).
FYLOGENEETTINEN PUU
https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-4-11/figures/2
Phylogenetic analysis showing relationships between human Kelch protein family members.
(A) Phylogenetic tree of full-length amino acid sequences of human proteins were aligned.
(B) Phylogenetic tree of amino acid sequences of Kelch domains.
Phylogenetic trees were constructed by maximum-likelihood method using
BLOSUM matrix in MEGA 6.06. Reference sequences used for alignments are
indicated at right of each protein name. Blue highlighting indicates
KBTBD subfamily members; green indicates KLHDC subfamily members. *,
proteins involved in NMD neuromuscular diseases; **, family members
implicated in cancer; #, proteins whose defects cause other inherited
diseases (Table 2). Scale bars indicate relative distances and represent the degree of differences between the sequences.
Domeenien selitykset :
BTB/POZ domain (N-terminal)
The BTB/POZ domain derives its name from the Drosophila Bric-a-brac, Tramtrac, and Broad complex due to sequence homology[62, 63]. As the DNA poxvirus in which this domain was first identified also showed some similarity to zinc finger proteins, this domain was concurrently named the POZ (Poxvirus and Zinc finger) domain.
BTB domains are mainly involved in facilitating self-oligomerization or mediating protein-protein interactions with other proteins[64, 65]. Despite the similar secondary structures and shared organization of BTB proteins, their primary sequences are not well conserved. This sequence variability between BTB proteins contributes to differential protein-protein interactions and results in different functional roles. BTB domains are also present in other non Kelch-repeat containing proteins. The major difference lies in the protein interactors of BTB domains in Kelch versus non-Kelch proteins.
In the Kelch family, the most important known interactive role of the BTB domain is to act as an adaptor between E3 ubiquitin ligases and Kelch domains in order to form active ubiquitination complexes[66–68].
In non-Kelch families of proteins, BTB protein-regulated interactions typically involve recruitment of co-activators or repressors to transcription complexes. In addition, these interacting proteins are also involved in cytoskeletal arrangement and ion conductance[69–72].
BACK domain
The BACK domains found in KLHL subfamily members are the most conserved domain of the Kelch family and are present between the N-terminal BTB and C-terminal Kelch domains. BACK domains contain an N-terminal conserved Asn-Cys-Leu-Gly-Ile motif (NCLGI) and a Val-Arg-[Leu/Met/Phe]-Pro-Leu-Leu sequence, two arginines (R) , four glutamic acids (E) , and several hydrophobic positions causing them to be hydrophobic in nature[61]. The true role of the BACK domain is not known, but it is predicted to participate in BTB-E3 ubiquitin ligase complex formation[61]. Evidence for the functional significance of BACK domains comes from recent studies where missense mutations in this domain in KLHL40 and KLHL41 are pathogenic in human patients affected with nemaline myopathy[14, 22].
Kelch domain (C-terminal) ( Each kelch repeat forms a blade of beta propeller )
Kelch motifs range from 44 to 56 amino acids in length and are usually arranged in a series of five to seven repeats in most of the family members[23]. The signature motifs in each Kelch repeat are a series of four hydrophobic amino acids followed by glycine doublet (GG), a conserved tyrosine(Y), and a conserved tryptophan (W). Each Kelch repeat folds into four twisted antiparallel β-strands connected by intrablade loops to form a single blade of a β-propeller (Figure 1B). A C-terminal strand closure mechanism links the first and last blades to complete the propeller. Kelch β-propellers primarily function as scaffolds for protein-protein interactions. Despite the shared tertiary structure, there is little primary sequence identity between one Kelch repeat and another, suggesting a wide diversity of interacting partners across the Kelch superfamily. In nemaline myopathy, all pathogenic KBTBD13 mutations identified to date in human patients were found in the Kelch repeats[21]. Similarly, mutations in Kelch repeats of both KLHL40 or KLHL41 also result in nemaline myopathy[14, 22].
KELCH1 geenin koodaama proteiini on neuronaalinen ja moduloi P/Q-tyyppisiä kalsiumkanava virtoja.
https://pubmed.ncbi.nlm.nih.gov/17289272/
Kohdennettu deleetio
- PMID: 17289272
- DOI: 10.1016/j.neuroscience.2006.12.046
The Kelch-like protein 1 modulates P/Q-type calcium current density. KLHL1
on aivospesifinen j muodostaa multimeerejä sekä kykenee sitomaan
aktiinifilamentteja. Se on sytosolinen ja moduloinee neuronien kasvuia,
dendriitipäiden dynamisto morfologiaa tai se toimii postsynaptiselle
funktiolle essentiellien neuronissa johtaa dendriittien vajeeseen
näissä neuroneissa, kävely muuttuu epänormaaliksi ja koeläin hiiri
menettää motorisen kooridaationsa.
- The actin-binding protein Kelch-like 1 (KLHL1) is a neuronal protein that belongs to the evolutionarily-conserved Kelch protein super-family. The mammalian KLHL1 is brain-specific, cytosolic and can form multimers and bind actin filaments. KLHL1's function is likely that of an actin-organizing protein, possibly modulating neurite outgrowth, the dynamic morphology of dendritic spine heads; or anchoring proteins essential for post-synaptic function, like ion channels. Targeted deletion of the KLHL1 gene in Purkinje neurons results in dendritic deficits in these neurons, abnormal gait, and progressive loss of motor coordination in mice [He Y, Zu T, Benzow KA, Orr HT, Clark HB, Koob MD (2006)
Kohdennettu deleetio yksittäisen SCA8 ataxialokuksen alleelissa hiirellä aiheuttaa epänormaalin kävelyn,motorisen koordinaation lisääntyvän menetyksen ja Purkijen solujken dendriittien vajeen.
- Targeted deletion of a single SCA8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficits. J Neurosci 26:9975-9982].
Nyt tiedemiesryhmä testasi tämän hypoteesin: KLHL1 saattaa tehdä interaktion ja moduloida jännitteestä riippuvia kalsiumkanavia. He mittasivat KLHL1 interaktion P/Q-tyyppisten kanavien pääasialliseen alayksikköön alfa1A. Kokeiluisssa käytettiin alkion munuaislinjan solua (HEK293) sekä pikkuaivojen primääriviljelmiä ja havaittiin samanaikaisilmenemää alfa (1A) - ja KLHL1- immunoreaktiviteeteissä sekä proteiinien endogeenisillä että merkatuilla versioilla.
- Here we tested the hypothesis that KLHL1 may interact and modulate voltage-gated calcium channels by assessing the interaction of the principal subunit of P/Q-type channels, alpha(1A), with KLHL1. Experiments in human embryonic kidney line HEK 293 (HEK) cells and cerebellar primary cultures revealed co-incidence of alpha(1A) and KLHL1 immunoreactivity when testing both the endogenous or epitope-tagged versions of the proteins.
Samanaikaista immunosaostumista havaittiin tapahtuvan ( HEK)-munuaissoluissa ja aivokudossoluissa KLHL1 altistuksessa FLAG-merkatuissa tai Alfa(1A)-vasta-aineilla immunosaostetuissa näytteissä.
- Similarly, co-immunoprecipitation experiments in HEK cells and brain tissue exposed the presence of KLHL1 in protein samples immunoprecipitated with FLAG-tagged or alpha(1A) antibodies.
Toiminnalliset tutkimukset KLHL1:n vaikutuksesta P/Q-tyyppisiin virtausominaisuuksiin (tietyissö solututkimuksissa testattuna) osoitti merkitsevää keskimääräisen virrantiheyden lisääntymistä KLHL1:n läsnäolon vaikutuksesta ( 80% lisääntymä) samoin tapahtui aktivaatiotilan muutota.
- Functional studies of KLHL1 on P/Q-type current properties probed with whole-cell patch clamp revealed a significant increase in mean current density in the presence of KLHL1 (80% increase; from -13.2+/-2.0 pA/pF to -23.7+/-4.2 pA/pF, P<0.02), as well as a shift in steady state activation V(50) of -5.5 mV (from 12.8+/-1.8 mV to 7.3+/-1.0 mV, P<0.02).
Tiedemiesryhmän yhteenvetona on havaittu johdonmukainen KLHL1 vaikutus Proliini/glutamiini-tyyppisen kalsiumkanavan funktiossa ja he ehdottavat mahdollisen uuden osan KLHL1:lle solun excitabiliteetissä, ärtyvyydessä.
- Our data are consistent with a modulatory effect of KLHL1 on
the P/Q-type calcium channel function and suggest a possible novel role
for KLHL1 in cellular excitability.
Oma kommentti: Gluteeni-intoleranssissa esiintyvät toksiset peptidit sisältävät paljon monenlaisia PQ pätkiä, joita ei keliaakikko saa entsymaattisesti sulatettua ravinnosta ja siksi on gluteeniton dieetti apuna. Myös neorotoksiset virukset sisältävät runsaasti pilkkoutumattomia QQQQ jaksoja.
Glutamiinista Q muodostuva glutamiinihappo E on excitatorinen, glutamiini Q ei ole excitatorinen. näistä metaboloituva GABA on inhibitorinen. Proliini voi muutua aineenvaihdunnassa glutamiinihapoksi. Harmaan aivosolun tärkein metabolinen sykli on näiden aminohappojen E,Q, GABA, alfa-Ketoglutaraatti, gamma-OH-butyraatti ( aivojen väsymys ja uniaine). Glutamiini voi pilkkoa aminoryhmän , joka antaa "ilmaisenergiaa" synteseihin. Tällä kierrolla aivot fiksoivat irtoavaa ammoniumia,joka on toksinen. Vapaa kalsiumjoni on myös toksinen ja glutamiinihappo voi gammakarboksyloitua ja fiksoida vapaata kalsiumia. Tähän K1-vitamiini muodostaa aivojen alueella spesifisen MK4 kokoisen menakinonin. Muistiin 8.3. 2024
Otan tähän teidon myös tuosta P/Q kalsiumkanavasta: Sillä on erityinen geeninimi CACNA1A
-
Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]
GeneCards Summary for CACNA1A Gene
CACNA1A (Calcium Voltage-Gated Channel Subunit Alpha1 A) is a Protein Coding gene. Diseases associated with CACNA1A include Spinocerebellar Ataxia 6 and Episodic Ataxia, Type 2. Among its related pathways are DREAM Repression and Dynorphin Expression and TCR Signaling (Qiagen). Gene Ontology (GO) annotations related to this gene include monoatomic ion channel activity and voltage-gated calcium channel activity. An important paralog of this gene is CACNA1B.
UniProtKB/Swiss-Prot Summary for CACNA1A Gene
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282) (By similarity). They are however insensitive to dihydropyridines (DHP). ( CAC1A_HUMAN,O00555 )
-
Voltage-gated calcium channels (CaV) are present in the membrane of most excitable cells and mediate calcium influx in response to depolarization. They regulate intracellular processes such as contraction, secretion, neurotransmission and gene expression.
Inga kommentarer:
Skicka en kommentar