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KLHL28

Sequential rainbow 3D tertiary protein structure of human KLHL28 modeled using NCBI Structure.

Overview

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 is comprised of 42 different genes. Aberrant activation of KLHL28 results in increased likelihood of hypertension, hyperkalemia, and cancer. The KLHL28 gene, also known as BTBD5, has orthologs in vertebrates and some marine invertebrates, and has been well-conserved over evolutionary timescales.

Gene

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).

Transcription Factors

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

High-scoring 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

Mutations

mRNA and Transcriptional Variants

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. 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

The predicted secondary mRNA structure for the human KLHL28 3’ untranslated region (UTR) created using RNAstructure. 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

RNA Binding Protein Interactions

An analysis of the miRNA binding capacity of the KLHL28 isoform 1 transcript returned with only one conserved miRNA target conserved through mammals present in the 3' UTR. The miRNA, hsa-miR-182-5p, has been associated with tumorigenesis, specifically in lung tissue.

RNA binding protein 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. Based on these highly likely RNA binding proteins, KLHL28 expression at the RNA level is predicted to be connected to neural development during embryogenesis and differentiation.

Protein

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

Amino Acid Composition

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

Comparing amino acid composition of the KLHL28 isoform 1 protein and protein domains between Homo sapiens orthologs using statistical analysis of protein sequences (SAPS). 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. The broad-complex, tramtrack, and bric-á-brac (BTB) and BACK 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

The protein can be broken down into eight subdomains: 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 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

A schematic of the protein domains and predicted post-translational modifications for human KLHL28 created using IBS2.0. Red markers indicate phosphorylation sites.

Tertiary Structure

Protein Localization

Function

Protein-Protein Interaction Network

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.

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

Evolution

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

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

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

References

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