Trends in Biochemical Sciences
FrontlinesCytoplasmic regulatory functions of the KH-domain proteins hnRNPs K and E1/E2
Section snippets
KH domains, a structural basis for RNA binding
The KH domain was initially defined in hnRNP K as a conserved region of 45–55 amino acid residues that is repeated three times in this protein7, 8. On the basis of RNA-binding and NMR studies, estimates of the length of a KH domain were later revised to 65–70 residues9, 10(see below).
KH domains are present in numerous proteins. Notable examples are vigilin (which consists of 15 KH domains)[10], nova (a neuron-specific three-KH-domain protein)[11]and FMR1 (which contains two KH domains)[12].
hnRNP K
hnRNP K was first characterized as a component of the hnRNP particle[16]. It contains other recognized sequence motifs in addition to KH domains. KH-domains 1 and 2 of hnRNP K are separated from domain 3 by several different motifs. The first contains two RGG boxes[16]. The second comprises proline-rich SH3-domain-interaction motifs; these proline-rich motifs bind to the proto-oncogene products SRC17, 18, FYN (Ref. [18]), LYN (Ref. [18]) and VAV19, 20(Table 1). The third motif contains binding
Unexpected cytoplasmic functions of hnRNPs K, E1 and E2
hnRNPs K and E1/E2 function as regulators of cytoplasmic mRNAs, particularly in erythroid cells. Reticulocyte 15-lipoxygenase (LOX) is a key enzyme in erythroid-cell differentiation. It catalyses the dioxygenation of intact phospholipids in mitochondrial membranes and participates in their breakdown in the final steps of erythrocyte maturation[28].
LOX mRNA, a highly abundant message in erythroid-precursor cells in the bone marrow, is translationally silenced until enucleated reticulocytes in
Concluding remarks
The hnRNPs K, E1 and E2 have now been implicated in the regulation of gene expression at nearly all levels: transcription, mRNA processing, mRNA transport, mRNA stability and translation. Such a broad involvement suggests that they act as bridging molecules that facilitate the association of proteins in multicomponent regulatory systems. hnRNP K enables proteins that do not bind to nucleic acids to join complexes containing mRNA directly. For example, VAV, a hematopoietic cell-specific
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