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KLHL28

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KLHL28
Identifiers
AliasesKLHL28, BTBD5, kelch like family member 28
External IDsMGI: 1913939; HomoloGene: 23036; GeneCards: KLHL28; OMA:KLHL28 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

54813

66689

Ensembl

ENSG00000179454

ENSMUSG00000020948

UniProt

Q9NXS3

Q9CR40

RefSeq (mRNA)

NM_001308112
NM_017658

NM_025707

RefSeq (protein)

NP_001295041
NP_060128

NP_079983

Location (UCSC)Chr 14: 44.92 – 45.04 MbChr 12: 64.99 – 65.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Sequential rainbow 3D tertiary protein structure of human KLHL28 modeled using NCBI Structure.[5]

Kelch-like Homolog 28 (KLHL28) is a protein that is encoded by the KLHL28 gene in humans. It is a member of the Kelch-like gene family, which comprises 42 different genes.[6] Aberrant activation of KLHL28 results in increased likelihood of hypertension, hyperkalemia, and cancer.[7] The KLHL28 gene, also known as BTBD5, has orthologs in vertebrates and some marine invertebrates, and has been well-conserved over evolutionary timescales.

Gene

[edit]

The KLHL28 gene is located on the negative strand of human Chromosome 14 (14q21.2) and spans 7019 base pairs in its complete isoform (isoform 1).[8]

Transcription factors

[edit]

Hundreds of transcription factors are predicted to bind to the promoter region. Many of the highly scored transcription factors from the JASPAR database via the University of California, Santa Cruz Genome Browser are listed in the table below.[9]

Transcription Factors for Human KLHL28
Transcription Factor Binding Region Strand Function
ZNF652 (Zinc Finger Protein 652) aagagtt + Transcription repressor
FOXH1 (Forkhead Box H1) aatcccaa - Transcription in nodal expression
ETV4 (ETS Variant 4) accggagct + Promotes proliferation
FEZF2 (FEZ Family Zinc Finger 2) cccagg + Regulates corticospinal motor neuron genes
TGIF2LY (TGFB Induced Factor Homeobox 2-like Y-linked) ctccagttgtcc + Regulates RNA Polymerase II in males
TGIF2 (TG-Interacting Factor 2) tgaccacgatct - Regulates brain development
ZBED4 (Zinc Finger BED-Type Containing 4) ttctctccgc - Regulates genes involved in retinal function
ZNF708 (Zinc Finger Protein 708) tgtagaa - Regulates RNA Polymerase II, carcinoma
ELF1 (E74-like ETS TF1) ctaggaaag - Regulates homeostasis and vascular development
Msgn1 (Mesogenin 1) cacaaatcgg + Regulates mesoderm fate
KLF2 (Krüppel-like Factor 2) ccccgg - Regulates differentiation
ELK1 (ETS-like Kinase 1) aaat - Regulates early gene experession via serum response
KLF14 (Krüppel-like Factor 14) tggga - Regulates lipid metabolism
SP4 (Specificity Protein 4) gtag - Regulates cytochrome C in primary neurons
Spi1 (Spleen Focus Forming Virus Proviral Integration Oncogene) aaagaaatgttgc - Regulates development and function of microglia
TBX20 (T-Box TF20) taggtctgttt + Regulates cardiac development
ZNF530 (Zinc Finger Protein 530) ggcggagagggaa - Regulates RNA Polymerase II
MAZ (Myc-associated Zinc Finger Protein) cccctccg + Regulates transcription in neural stem cells
ZNF263 (Zinc Finger 263) gggaggc - Upregulates IL-33, promotes lung cancer
SPIB (Spi-B TF) tcacttgcggt + Regulates M-cell differentiation

Expression

[edit]

KLHL28 is ubiquitously expressed under normal physiological conditions in humans and has been found not to be monallelically expressed.[10] DNA microarray data also suggests that gene expression of KLHL28 is elevated in the brain and heart.[11]

Under hypoxic conditions, DNA microarray data illustrated increased expression of KLHL28.[12] Further, in a DNA microarray study of small-cell lung cancer, KLHL28 was expressed at significantly higher levels than the control.[13] These data indicate that the gene's transcription is impacted by the tumor microenvironment, which is typically not well-vascularized and often hypoxic.

Mutations

[edit]

Missense single nucleotide polymorphisms (SNPs) have been identified in both the coding and noncoding regions of the gene.[14][15] The SNPs with the potential for most clinical significance are those affecting the composition of the KLHL28 protein, specifically within Kelch motif 1 (rs117295933, C>A / C>G / C>T) and motif 3 (rs35352691, T>G).

mRNA and transcriptional variants

[edit]
Transcript variants and protein isoforms of the KLHL28 gene in Homo sapiens. Blue boxes indicate the exon is present in the transcript variant, while red boxes indicate the exon is absent.

There are a total of seven transcriptional variants: two isoforms and five spliced transcript variants, all of which are based on the longest transcript, isoform 1. Isoform 1 contains five exons, and all transcriptional variants contain at least exon 2. The six conserved Kelch motifs in the KLHL28 protein are found through the end of exon 2 through exon 5.

The predicted secondary mRNA structure for the human KLHL28 5’ untranslated region (UTR) created using RNAstructure.[16] The folding free energy of this structure is -122.6 kcal/mol. A) Zoomed-out view of the entire 5’ UTR. B) An enhanced image of the UTR start and end (ATG in green) and conserved stem-loop structures (red boxes).

5' Untranslated region

[edit]

The 5' untranslated region (5' UTR) of KLHL28 is well-conserved amongst orthologs, similar to the protein sequence. Demonstrating this conservation, the transcription factor ZNF263 was conserved after a five-member mammalian multiple sequence alignment (MSA) using the orthologs golden snub-nosed monkey, green monkey, southern pig-tailed macaque, and thirteen-lined ground squirrel.

The predicted secondary mRNA structure for the human KLHL28 3’ untranslated region (UTR) created using RNAstructure.[17] The folding free energy of this structure is -748.2 kcal/mol. A) Zoomed-out view of the entire 3' UTR. B) An enhanced image of the 3’ UTR start. C) An enhanced image of the polyA site (blue box). D) An enhanced image of a section of stem-loops strongly conserved across simulated structural models.

3' Untranslated region

[edit]

A four-member MSA was run for the 3' UTR and found that, like the 5' UTR, it was strongly conserved across primates, with the same orthologs as in the 5' UTR section, minus the thirteen-lined ground squirrel.

RNA binding protein interactions

[edit]

An analysis of the miRNA binding capacity of the KLHL28 isoform 1 transcript returned with only one miRNA target that was found on the 3' UTR and conserved through mammals.[18] The miRNA, hsa-miR-182-5p, has been associated with tumorigenesis, specifically in lung tissue.[19]

RNA binding protein binding capacity for the 3' UTR of human KLHL28 was assessed and returned with 12 repeats of ELAVL2, 2 of SNRPA, 3 of ZFP36, and 1 of pum.[20] Based on these highly probable predicted RNA binding proteins, KLHL28 expression at the RNA level is predicted to be connected to neural development during embryogenesis and differentiation.[21][22][23][24]

Protein

[edit]
Amino acid composition of human KLHL28 using statistical analysis of protein sequences (SAPS) online tool.[25] A) Entire KLHL28 protein. B) BTB domain. C) Kelch region.

Amino acid composition

[edit]

The KLHL28 gene encodes the KLHL28 protein which is 585 amino acids long and has a molecular weight of 65.8kDa.[8] The theoretical isoelectric point (Ip) was predicted to be 5.90 based on the amino acid composition.[26]

Comparing amino acid composition of the KLHL28 isoform 1 protein and protein domains between Homo sapiens orthologs using statistical analysis of protein sequences (SAPS).[27] Green indicates the amino acid is rich in the protein/domain, while red indicates it is poor. Color intensity corresponds to how rich/poor, with - and + being the lightest and -- and ++ being darkest.

An analysis of the whole protein indicated that it is tyrosine-rich (5.3%); however, amino acids at the domain level were expressed differently.[28] The broad-complex, tramtrack, and bric-á-brac (BTB) and BACK (BTB and C-terminal Kelch) domains were extremely glycine-poor (2.4%) and also histidine-rich (4.7%). On the other hand, the Kelch domains were rich in both valine (9.7%) and tyrosine (5.6%).

Protein domains

[edit]

The protein can be broken down into eight domains: the Broad-complex, Tramtrack, and Bric-á-brac (BTB) domain (amino acids 31-148); the BACK domain (amino acids 151-253); and Kelch domains 1 (amino acids 298-345), 2 (amino acids 346-400), 3 (amino acids 401-444), 4 (amino acids 445-493), 5 (amino acids 494-541), 6 (amino acids 542-585). The high predicted isoelectric point of Kelch domain 3 indicates it may have an important role in forming the Cullin3-RING E3 ubiquitin ligase complex.

Annotated Protein Domains in KLHL28
KLHL28 pI MW (in kDa) Residues
Whole Protein 5.90 65.8 585
BTB Domain 4.92 13.2 118
BACK Domain 4.43 13.1 113
Kelch 1 4.11 5.3 48
Kelch 2 5.71 6.1 55
Kelch 3 8.95 4.9 44
Kelch 4 5.38 5.4 49
Kelch 5 7.02 5.4 48
Kelch 6 5.30 4.8 44

Post-translational modifications

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Predicted post-translational modifications (PTMs) of the protein include a number of phosphorylation sites, visualized in the linear protein schematic to the right.[29][30][31]

A schematic of the protein domains and predicted post-translational modifications for human KLHL28 created using IBS2.0. Red markers indicate phosphorylation sites.
Visualizations of human KLHL28 protein using NCBI Structure: A) Charge; B) Hydrophobicity; C) Kelch motifs, highlighted in yellow; D) Rainbow, N to C terminus; E) Rainbow sphere; and F) Secondary structure.

Tertiary structure

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The BTB and BACK domains are predicted with high confidence to mostly fold into alpha helices. Meanwhile, the Kelch domains in the protein form into beta sheets, which are then expected to complex into a beta barrel.[32] No hydrophobic regions were identified on the protein, indicating that it is most likely not cell or organelle membrane-localized.

Protein localization

[edit]

KLHL28 protein is soluble, localized in the cytoplasm, and is predicted to contain a nuclear localization signal.[33][34]

Function

[edit]

Based on the protein-protein interaction (PPI) network below, the KLHL28 protein is predicted to play a critical role in the formation and function of the E3 ubiquitin ligase complex involved in protein degradation and recycling.[35] Additionally, the component domains of the protein suggest it may also be involved in orienting the substrate protein entering the Cullin3-based E3 ligase complex.[36]

Protein-protein interaction network

[edit]

The majority of identified proteins found to interact with the KLHL28 protein in humans are involved in the E3 ubiquitin ligase structure. The table below illustrates proteins interacting with human KLHL28 protein and their detection methods based on a consensus of high-throughput screening data reported from STRING, BioGRID, MINT, and IntAct databases.[37][38][39][40]

KLHL28 Protein-Protein Interaction Network
Gene Localization Detection Method Function
CUL3 (Cullin-3)[41] Cytosol/nucleus Affinity capture-MS Core component of E3 ubiquitin ligase complex
AKAP11 (A-Kinase Anchoring Protein-11)[42] Cytosol/nucleus Affinity capture-MS Enables protein kinase A binding in somatic and germ cells
CUL7 (Cullin-7)[43] Cytosol/nucleus/Golgi Affinity capture-MS Aids in E3 ubiquitin ligase assembly
FBXL17 (F-Box and Leucine-rich Repeat Protein 17)[44] Cytosol/nucleus Affinity capture-MS Forms SCF complexes, acts as protein ubiquitin ligases
IPP (Inracisternal A Particle-promoted Polypeptide)[45] Cytosol/cytoskeleton Affinity capture-MS Actin organization
KLHL13 (Kelch-like Homolog 13)[46] Cytosol/mitochondrion Affinity capture-MS Aids in E3 ubiquitin ligase assembly, necessary for chromosome segregation
KLHL14 (Kelch-like Homolog 14)[47] ER/cytoskeleton/cytosol Affinity capture-MS Tumor suppressor, promotes ubiquitination of B cell receptors
KLHL21 (Kelch-like Homolog 21)[48] Cytoskeleton/cytosol Affinity capture-MS Implicated with ubiquitin protein transferase activity
NSP1 (Novel SH2-containing Protein 1)[49] Cytosol/nucleus Two-hybrid May play a role in JNK (Jun N-terminal kinase) activation under stress conditions

Evolution

[edit]

Based on the ortholog data in the table below, the KLHL28 gene first appeared in some marine invertebrates nearly 700 million years ago. The gene is found in some mollusks, cnidarians, and echinoderms, but not in arthropods nor cephalopods. Other members of the gene family (paralogs of KLHL28, such as KLHL20) have been identified in plants, bacteria, and archaea, indicating that the Kelch-like homologs are highly conserved across evolutionary time and likely serve an important role.

Unrooted phylogenetic tree illustrating KLHL28 gene similarity across evolutionary time and groups. M. fascicularis is Crab-eating macaque, L. canadensis is Canada lynx, M. musculus is Mouse, T. alba is Barn owl, S. humboldti is Humboldt penguin, A. sagrei is Brown anole, T. sirtalis is Garter snake, C. aspera is Ground boa, B. bufo is Toad, L. chalumnae is Coelacanth, and D. rerio is Zebrafish.
A scatterplot graph comparing the corrected divergence (m) between human KLHL28 and its orthologs (blue triangles), human Cytochrome C (orange circles), and human Fibrinogen a (green squares).

Orthologs

[edit]
Selected Orthologs of KLHL28
Common Name Taxonomic Group Median Date of Divergence (MYA) Protein Accession # Sequence Length (aa) Identity to Human (%) Similarity to Human (%)
Human Primates 0 NP_001295041.1 585 100.0 100.0
Crab-eating Macaque Primates 28.8 XP_015308707.1 585 99.2 99.3
Canada Lynx Carnivora 94 XP_030174874.1 571 98.8 97.3
Sack-winged Bat Chiroptera 94 XP_066133942.1 571 96.3 97.1
House Mouse Rodentia 87 NP_079983.1 571 97.0 96.8
Orca Artiodactyls 94 XP_004270054.1 571 99.1 96.2
Koala Diprotodontia 160 XP_020842083.1 645 93.2 84.8
Common Garter Snake Squamata 319 XP_013915426.1 571 87.7 95.4
Brown Anole Squamata 319 XP_060644111.2 571 87.0 95.0
Papuan Ground Boa Squamata 319 XP_063146665.1 571 87.6 92.3
American Alligator Crocodilia 319 KYO47230.1 585 93.2 92.0
Kori Bustard Otidiformes 319 NXE21565.1 577 92.5 95.6
Humboldt Penguin Sphenisciformes 319 KAF1420631.1 577 92.2 95.2
Barn Owl Strigiformes 319 XP_042655085.1 571 92.5 94.9
Chicken Galliformes 319 XP_015132273.1 571 92.6 91.8
Gaboon Caecilian Gymnophiona 352 XP_033809266.1 574 92.5 95.0
American Toad Anura 352 XP_040267576.1 571 88.1 92.1
Coelacanth Latimeriodei 415 XP_064420773.1 571 88.4 92.3
Zebrafish Cypriniformes 429 XP_017207216.1 571 83.2 90.4
Small-toothed Sawfish Rhinoprisitiformes 462 XP_051874951.1 571 85.1 89.7
Great White Shark Lamniformes 462 XP_041069815.1 571 85.5 89.9
Sea Lamprey Petromyzontiformes 563 XP_032831289.1 611 61.4 71.0
European Lancelet Amphioxiformes 581 XP_066281657.1 574 56.6 70.3
Crown-of-thorns Starfish Valvatida 619 XP_022083107.1 576 53.3 67.9
Branching Stony Coral Scleractinia 685 XP_029214089.1 570 49.7 65.8
Chiton Chitonida 686 XP_064600849.1 521 47.8 55.5

Paralogs

[edit]
Selected Paralogs of KLHL28
Gene Name Protein Accession # Sequence Length (aa) Identity to KLHL28 (%) Similarity to KLHL28 (%)
KLHL28 NP_001295041.1 585 100.0 100.0
KLHL5 NP_001007076.1 709 39.9 57.4
KLHL3 NP_059111.2 587 38.7 54.9
KLHL20 NP_055273.2 609 42.8 54.3
KLHL17 NP_938073.1 642 41.7 54.5
KLHL1 NP_066917.1 748 40.6 53.5

Clinical significance

[edit]

Based on the function of its encoded protein in protein breakdown and recycling, the KLHL28 gene has a strong clinical significance. Furthermore, the expression data in hypoxic and cancerous conditions suggests the Cullin3-RING E3 ubiquitin ligase complex is involved in protein homeostasis, which can be sabotaged in cancerous cells.[50] Consequently, the KLHL28 gene and its interaction network represent novel targets for gene therapy cancer treatments.

References

[edit]
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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020948 – Ensembl, May 2017
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  50. ^ Xiang, Senfeng; Shi, Xiaoxian; Chen, Pengfei; Chen, Yifan; Bing, Shaowei; Jin, Xizhi; Cao, Ji; Wang, Jinhu; Yang, Bo; Shao, Xuejing; He, Qiaojun; Ying, Meidan (2021-07-01). "Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy". Pharmacological Research. 169: 105616. doi:10.1016/j.phrs.2021.105616. ISSN 1043-6618. PMID 33872809.
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