Summary: KH domain
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KH domain Edit Wikipedia article
Structure of a KH domain from the human protein vigilin.
|SCOPe||1vig / SUPFAM|
The K Homology (KH) domain is a protein domain that was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. An evolutionarily conserved sequence of around 70 amino acids, the KH domain is present in a wide variety of nucleic acid-binding proteins. The KH domain binds RNA, and can function in RNA recognition. It is found in multiple copies in several proteins, where they can function cooperatively or independently. For example, in the AU-rich element RNA-binding protein KSRP, which has 4 KH domains, KH domains 3 and 4 behave as independent binding modules to interact with different regions of the AU-rich RNA targets. The solution structure of the first KH domain of FMR1 and of the C-terminal KH domain of hnRNP K determined by nuclear magnetic resonance (NMR) revealed a beta-alpha-alpha-beta-beta-alpha structure. Autoantibodies to NOVA1, a KH domain protein, cause paraneoplastic opsoclonus ataxia. The KH domain is found at the N-terminus of the ribosomal protein S3. This domain is unusual in that it has a different fold compared to the normal KH domain.
Nucleic acid binding
KH domains bind to either RNA or single stranded DNA. The nucleic acid is bound in an extended conformation across one side of the domain. The binding occurs in a cleft formed between alpha helix 1, alpha helix 2 the GXXG loop (contains a highly conserved sequence motif) and the variable loop. The binding cleft is hydrophobic in nature with a variety of additional protein specific interactions to stabilise the complex. Valverde and colleagues note that, "Nucleic acid base-to-protein aromatic side chain stacking interactions which are prevalent in other types of single stranded nucleic acid binding motifs, are notably absent in KH domain nucleic acid recognition".
Structurally there are two different types of KH domains identified by Grishin which are called type I and type II. The type I domains are mainly found in eukaryotic proteins, while the type II domains are predominantly found in prokaryotes. While both types share a minimal consensus sequence motif they have different structural folds. The type I KH domains have a three stranded beta-sheet where all three strands are anti-parallel. In the type II domain two of the three beta strands are in a parallel orientation. While type I domains are usually found in multiple copies within proteins, the type II are typically found in a single copy per protein.
Human proteins containing this domain
AKAP1; ANKHD1; ANKRD17; ASCC1; BICC1; DDX43; DDX53; DPPA5; FMR1; FUBP1; FUBP3; FXR1; FXR2; GLD1; HDLBP; HNRPK; IGF2BP1; IGF2BP2; IGF2BP3; KHDRBS1; KHDRBS2; KHDRBS3; KHSRP; KRR1; MEX3A; MEX3B; MEX3C; MEX3D; NOVA1; NOVA2; PCBP1; PCBP2; PCBP3; PCBP4; PNO1; PNPT1; QKI; SF1; TDRKH;
- GarcÃa-Mayoral MF, Hollingworth D, Masino L, et al. (April 2007). "The structure of the C-terminal KH domains of KSRP reveals a noncanonical motif important for mRNA degradation" (PDF). Structure. 15 (4): 485â€“98. doi:10.1016/j.str.2007.03.006. PMID 17437720.
- Musco G, Kharrat A, Stier G, et al. (September 1997). "The solution structure of the first KH domain of FMR1, the protein responsible for the fragile X syndrome". Nat. Struct. Biol. 4 (9): 712â€“6. doi:10.1038/nsb0997-712. PMID 9302998.
- Baber JL, Libutti D, Levens D, Tjandra N (June 1999). "High precision solution structure of the C-terminal KH domain of heterogeneous nuclear ribonucleoprotein K, a c-myc transcription factor". J. Mol. Biol. 289 (4): 949â€“62. doi:10.1006/jmbi.1999.2818. PMID 10369774.
- Grishin NV (February 2001). "KH domain: one motif, two folds". Nucleic Acids Res. 29 (3): 638â€“43. doi:10.1093/nar/29.3.638. PMC 30387. PMID 11160884.
- Valverde R, Edwards L, Regan L (June 2008). "Structure and function of KH domains". FEBS J. 275 (11): 2712â€“26. doi:10.1111/j.1742-4658.2008.06411.x. PMID 18422648.
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No Pfam abstract.
Musco G, Stier G, Joseph C, Castiglione Morelli MA, Nilges M, Gibson TJ, Pastore A; , Cell 1996;85:237-245.: Three-dimensional structure and stability of the KH domain: molecular insights into the fragile X syndrome. PUBMED:8612276 EPMC:8612276
Internal database links
|SCOOP:||GTP_EFTU KH_1 KH_4 KH_5 KH_6 MOEP19 MRP-S24 VAR1|
|Similarity to PfamA using HHSearch:||KH_4|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR004044
The K homology (KH) domain was first identified in the human heterogeneous nuclear ribonucleoprotein (hnRNP) K. It is a domain of around 70 amino acids that is present in a wide variety of quite diverse nucleic acid-binding proteins [ PUBMED:8036511 ]. It has been shown to bind RNA [ PUBMED:9302998 , PUBMED:10369774 ]. Like many other RNA-binding motifs, KH motifs are found in one or multiple copies (14 copies in chicken vigilin) and, at least for hnRNP K (three copies) and FMR-1 (two copies), each motif is necessary for in vitro RNA binding activity, suggesting that they may function cooperatively or, in the case of single KH motif proteins (for example, Mer1p), independently [ PUBMED:8036511 ].
According to structural analyses [ PUBMED:9302998 , PUBMED:10369774 , PUBMED:11160884 ], the KH domain can be separated in two groups. The first group or type-1 contain a beta-alpha-alpha-beta-beta-alpha structure, whereas in the type-2 the two last beta-sheets are located in the N-terminal part of the domain (alpha-beta-beta-alpha-alpha-beta). Sequence similarity between these two folds are limited to a short region (VIGXXGXXI) in the RNA binding motif. This motif is located between helice 1 and 2 in type-1 and between helice 2 and 3 in type-2. Proteins known to contain a type-2 KH domain include eukaryotic and prokaryotic S3 family of ribosomal proteins, and the prokaryotic GTP-binding protein era.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||RNA binding (GO:0003723)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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The KH domain is thought to be the second most prevalent RNA binding motif in proteins. The motif is characterised by a conserved GXXXGXXG in the middle of the domain. Structures of KH reveal that the KH domain is arranged as either a beta-alpha-alpha-beta-beta (mini-KH domain) or beta-alpha-alpha-beta-beta-alpha (maxi-KH domain). The secondary elements are separated by at least four loop segments. The second loop is located between beta-1 and al The KH domain can be found either as single or multiple copies. The KH domain usually binds RNA as a multimer.
The clan contains the following 14 members:DUF2096 DUF370 KH_1 KH_10 KH_2 KH_4 KH_5 KH_6 KH_7 KH_8 KH_9 MOEP19 MRP-S24 SLS
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Number in seed:||127|
|Number in full:||19271|
|Average length of the domain:||76.40 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||27.42 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||20|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the KH_2 domain has been found. There are 1242 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.