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Figure 1 . NCL tandem RBD models display high structural
similarities with existing individual NCL RBD crystal structures. A)Superposition of the modeled RBD1-4 (pale green) with individual crystal
structures of NCL RBD1 (PDB ID: 1FJ7 ;marine blue), RBD2 (PDB ID: 1FJC
deep salmon), RBD3 (PDB ID: 2FC9; Lightblue), and RBD4 (PDB ID: 2FC8;
deep olive). RMSD scores for RBD1, RBD2, RBD3, and RBD4 are 3.594 Å,
2.324 Å, 1.775 Å, and 2.442 Å, respectively. B) Superposition
of the modeled RBD3-4 (pale green) with individual structures of NCL
RBD3 (PDB ID: 2FC9; Lightblue), and RBD4 (PDB ID: 2FC8; deep olive) RMSD
scores for RBD3 and RBD4 are 0.956 Å and 1.753 Å, respectively.
Figure 2. Structural models of the miRNAs analyzed in this
study. Top ranked models for all 6 pri-miRNA (orange backbone with
bases shown in blue). Alternative miRNA models that exhibited
comparative evaluation profiles are shown in dark red.
Figure 3. Representative docking poses exhibiting binding mode 1
involving RBD3-4. A) Complete docking scenarios. B)Zoomed-in insets with intermolecular distances between residues
indicated. miRNA molecule backbone (orange), RBD1 (marine blue), RBD2
(deep salmon), RBD3 (light blue), RBD4 (deep olive). The linker regions
between RBDs 1 and 2, 3 and 4 are colored in green while the linker
between RBDs 2 and 3 are colored in yellow. Interacting nucleotides on
the miRNA and NCL-RBDs are indicated with deep teal and hot pink,
respectively.
Figure 4. Representative docking poses exhibiting binding mode 2
involving RBD4. A) Complete docking scenarios. B)Zoomed in version with intermolecular distances between residues
indicated. RBD1 (marine blue), RBD2 (deep salmon), RBD3 (light blue),
RBD4 (deep olive The linker regions between RBDs 1 and 2, 3 and 4 are
colored in green while the linker between RBDs 2 and 3 are colored in
yellow. Interacting nucleotides on the miRNA and NCL-RBDs are indicated
with deep teal and hot pink, respectively.
Figure 5. Representative docking poses exhibiting binding mode 3
involving RBD234. A) Complete docking scenarios. B)Zoomed in version with intermolecular distances between residues
indicated. RBD1 (marine blue), RBD2 (deep salmon), RBD3 (light blue),
RBD4 (deep olive). The linker regions between RBDs 1 and 2, 3 and 4 are
colored in green while the linker between RBDs 2 and 3 are colored in
yellow. Interacting nucleotides on the miRNA and NCL-RBDs are indicated
with deep teal and hot pink, respectively.
Figure 6. NCL residues predicted to interact with miRNAs A)
Comparison of hnRNP A1 RBDs with NCL RBDs (PDB ID: 6DCL). Beta strands
and RNP motifs are indicated with arrows. Known hnRNP A1 residues that
interact with ssDNA and miR-18 are indicated in light brown background.
NCL residues conserved in the equivalent positions are indicated in
yellow background. Conserved residues are indicated in bold and black
background. B) Summary of NCL-RBD residues most
frequently predicted to interact with miRNA based on docking . Different
types of interactions are indicated with background colors C)
Summary of predicted NCL-miRNA binding modes and a comparison with hnRNP
A1-miRNA binding model. 1) Known hnRNP A1-mir18 interaction
residues. 2) Proposed NCL-miRNA binding mode 1 where both
RBD3&RBD4 are involved in the interactions. 3) Proposed
NCL-miRNA binding mode 2 where RBD4 alone interacts with miRNA4) Proposed NCL-miRNA binding mode 3 which RBD3&4 and a single
residue from RBD2. Beta sheets are numbered on top, and residues
predicted to interact with miRNA are indicated in red. Newly identified
residues are indicated in black. The numbers indicate the position of
these residues in the corresponding beta strands.
Figure 7. Mapping of miRNA residues interacting with NCL. A)NCL contacts miRNA molecules at the UGU/GUG motifs closest to the loop.B) NCL contacts miRNA molecules on UGU/GUG motifs distant from
the loop and closer to GHG/CUC motifs. C) NCL contacts longer
miRNA molecules on UGU/GUG motifs slightly distant from the apical loop
and closer to the loop stem. Beta strands are numbered on top of the
arrowheads. RBD1 (marine blue), RBD2 (deep salmon), RBD3 (light blue),
RBD4 (deep olive), and linker loops between RBDs (neon green). UGU/GUG
motifs on miRNA that NCL interacts are indicated in green. miRNA
residues that NCL interacts with are but is not part of an UGG/GUG motif
is indicated in purple. UGU/GUG motifs on miRNA that NCL is not
interacting are indicated in red. GHG/CUC motifs are indicated in
orange.
Figure 8. Canonical and proposed models of NCL, Drosha, and
DGCR8 interactions with pri-miRNA molecules. A) Canonical
model involving Drosha & DGCR8-1and 252 B)Hypothetical model A where NCL-RBDs could replace DGCR8 – 2 C)Hypothetical model B where all MPC proteins and either one or both
NCL-RBDs interact with the pri-miRNA molecule. NCL-RBD3&4 are colored
in light blue and deep olive, respectively. DROSHA is light green.
DGCR8-1 is red, and DGCR8-2 is orange.