RESUMO
MicroRNAs (miRNAs) are a class of small regulatory noncoding RNAs that modulate the expression of their target genes through either mRNA degradation or inhibition of protein translation. In recent years, miRNAs have been shown to be critical regulators of hematopoiesis and have important roles in the differentiation of specific lineages. Here, we summarize our current understanding of miRNAs involved in hematopoiesis with a focus on the role of miRNAs in regulating erythroid and megakaryocytic differentiation and megakaryocyte-erythroid progenitor lineage commitment.
Assuntos
Diferenciação Celular/fisiologia , Eritrócitos/citologia , Megacariócitos/citologia , MicroRNAs/fisiologia , Linhagem da Célula , Humanos , MicroRNAs/genéticaRESUMO
FYVE domains are small zinc-finger-like domains found in many proteins that are involved in regulating membrane traffic and have been shown to bind specifically to phosphatidylinositol 3-phosphate (PtdIns-3-P). FYVE domains are thought to recruit PtdIns-3-P effectors to endosomal locations in vivo, where these effectors participate in controlling endosomal maturation and vacuolar protein sorting. We have compared the characteristics of PtdIns-3-P binding by the FYVE domain from Hrs-1 (the hepatocyte growth factor-regulated tyrosine kinase substrate) with those of specific phosphoinositide binding by Pleckstrin homology (PH) domains. Like certain PH domains (such as that from phospholipase C-delta(1)), the Hrs-1 FYVE domain specifically recognizes a single phosphoinositide. However, while phosphoinositide binding by highly specific PH domains is driven almost exclusively by interactions with the lipid headgroup, this is not true for the Hrs-1 FYVE domain. The phospholipase C-delta(1) PH domain shows a 10-fold preference for binding isolated headgroup over its preferred lipid (phosphatidylinositol 4,5-bisphosphate) in a membrane, while the Hrs-1 FYVE domain greatly prefers (more than 50-fold) intact lipid in a bilayer over the isolated headgroup (inositol 1,3-bisphosphate). By contrast with reports for certain PH domains, we find that this preference for membrane binding over interaction with soluble lipid headgroups does not require FYVE domain oligomerization.
Assuntos
Proteínas de Transporte de Cátions , Proteínas de Transporte de Monossacarídeos , Fosfatos de Fosfatidilinositol/metabolismo , Fosfolipídeos/metabolismo , Simportadores , Dedos de Zinco , Ligação Competitiva/genética , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Glutationa Transferase/genética , Fatores de Troca do Nucleotídeo Guanina , Células HeLa , Humanos , Lipossomos/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ligação Proteica/genética , Estrutura Terciária de Proteína/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Dedos de Zinco/genéticaRESUMO
Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns(3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.