Microprocessor complex

[2][3] The complex is minimally composed of the ribonuclease enzyme Drosha and the dimeric RNA-binding protein DGCR8 (also known as Pasha in non-human animals), and cleaves primary miRNA substrates to pre-miRNA in the cell nucleus.

[4][5][6] (DGCR8 is the name used in mammalian genetics, abbreviated from "DiGeorge syndrome critical region 8"; the homologous protein in model organisms such as flies and worms is called Pasha, for Partner of Drosha.)

The stoichiometry of the minimal complex was at one point experimentally difficult to determine, but it has been demonstrated to be a heterotrimer of two DGCR8 proteins and one Drosha.

[5][14] Microprocessor cleavage of pri-miRNAs typically occurs co-transcriptionally and leaves a characteristic RNase III single-stranded overhang of 2-3 nucleotides, which serves as a recognition element for the transport protein exportin-5.

[4][5][6] Hemin allows for the increased processing of pri-miRNAs through an induced conformational change of the DGCR8 subunit, and also enhances DGCR8's binding specificity for RNA.

The loop region of the pri-miRNA stem-loop is also a recognition element for regulatory proteins, which may up- or down-regulate microprocessor processing of the specific miRNAs they target.

[11] Microprocessor itself is auto-regulated by negative feedback through association with a pri-miRNA-like hairpin structure found in the DGCR8 mRNA, which when cleaved reduces DGCR8 expression.

A cryo-electron microscopy structure of the microprocessor complex, showing human Drosha protein ( ribonuclease III , green) and two subunits of DGCR8 (dark and light blue) interacting with and ready to cleave a primary microRNA . From PDB : 6V5B ​. [ 1 ]
A crystal structure of the human Drosha protein in complex with the C-terminal helices of two DGCR8 molecules (green). Drosha consists of two ribonuclease III domains (blue and orange); a double-stranded RNA binding domain (yellow); and a connector/platform domain (gray) containing two bound zinc ion (spheres). From PDB : 5B16 ​. [ 8 ]
The human exportin-5 protein (red) in complex with Ran-GTP (yellow) and a pre- microRNA (green), showing two- nucleotide overhang recognition element (orange). From PDB : 3A6P ​. [ 12 ]