KH domain

KH domain
Structure of a KH domain from the human protein vigilin.
Identifiers
Symbol	KH_1
Pfam	PF00013
Pfam clan	CL0007
ECOD	327.11.2
InterPro	IPR004088
SMART	KH
SCOP2	1vig / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1dt4​, 1dtj​, 1e3h​, 1e3p​, 1ec6​, 1j4w​, 1j5k​, 1k1g​, 1khm​, 1tua​, 1vig​, 1vih​, 1we8​, 1wvn​, 1x4m​, 1x4n​, 1ztg​, 1zzi​, 1zzj​, 1zzk​, 2axy​, 2ba0​, 2bl5​, 2cpq​, 2cte​, 2ctf​, 2ctj​, 2ctk​, 2ctl​, 2ctm​, 2fmr​, 2je6​, 2jea​, 2p2r​, 2pqu​, 2py9​, 2z0s​

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.^[1] 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.^[1] 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.^[2][3] 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.^[4]

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.^[5] 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".^[5]

Structurally there are two different types of KH domains identified by Grishin which are called type I and type II.^[4] 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.^[5]

AKAP1; ANKHD1; ANKRD17; ASCC1; BICC1; DDX43; DDX53; DPPA5; ERAL1; 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;