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Paralogs hnRNP L and hnRNP LL Exhibit Overlapping but Distinct RNA Binding Constraints

Smith, Sarah A., Ray, Debashish, Cook, Kate B., Mallory, Michael J., Hughes, Timothy R., Lynch, Kristen W.·2013·PLoS ONE
DOI 10.1371/journal.pone.0080701PMC PMC3823766
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Figure 1 Domain architecture and conservation of hnRNP L and hnRNP LL. Domain structure of hnRNP L (top) or hnRNP LL (bottom) showing total protein size and relative location and size of RNA-recognition motifs (RRMs) and linker regions (grey) including the glycine-rich (G) and proline-rich (P) segments of hnRNP L. Percent amino acid identity for each domain of hnRNP L compared to the respective domain of hnRNP LL is given between protein schematics.
Figure 1 Domain architecture and conservation of hnRNP L and hnRNP LL. Domain structure of hnRNP L (top) or hnRNP LL (bottom) showing total protein size and relative location and size of RNA-recognition motifs (RRMs) and linker regions (grey) including the glycine-rich (G) and proline-rich (P) segments of hnRNP L. Percent amino acid identity for each domain of hnRNP L compared to the respective domain of hnRNP LL is given between protein schematics.CC BY · PubMed Central
Figure 2 RNAcompete identifies overlapping but distinct k-mers as preferentially bound by hnRNP L and LL. (A) Top, position frequency matrix for the top ten heptamers in the total data set. Bottom, the ten heptamers (7-mers) with highest enrichment value (Z-score; numbers to right of sequences) in RNAcompete probe sets A and B with GST-hnRNP L. Z-score values were calculated as described previously [3]. CA dinucleotides are underlined. (B) Same as in panel A but with hnRNP LL. (C) The top ten octamers (8-mers) with highest enrichment value (Z-score; numbers to right of sequences) in the total RNAcompete data with GST-hnRNP L or (D) with hnRNP LL.
Figure 2 RNAcompete identifies overlapping but distinct k-mers as preferentially bound by hnRNP L and LL. (A) Top, position frequency matrix for the top ten heptamers in the total data set. Bottom, the ten heptamers (7-mers) with highest enrichment value (Z-score; numbers to right of sequences) in RNAcompete probe sets A and B with GST-hnRNP L. Z-score values were calculated as described previously [3]. CA dinucleotides are underlined. (B) Same as in panel A but with hnRNP LL. (C) The top ten octamers (8-mers) with highest enrichment value (Z-score; numbers to right of sequences) in the total RNAcompete data with GST-hnRNP L or (D) with hnRNP LL.CC BY · PubMed Central
Figure 3 Binding of hnRNP LL is more sensitive than hnRNP L to spacing of CA dinucleotides. (A) Complete sequence used for binding in panel B and as backbone for experiments in Figure 3 and 5. (B-F) Representative native gel analysis (EMSA) of purified, recombinant GST-tagged hnRNP L or Flag-tagged hnRNP LL incubated with radiolabeled T7-transcribed RNAs corresponding to a variant of the sequence in panel A. For each panel the sequence shown was substituted at the capitalized positions in panel A. CA dinucleotides are underlined, for panels C-F spacers between CAs are in red (N=spacer #). Affinities (Concentration of 50% binding = BC50) from at least three independent replicates of the EMSAs are shown below gels. Bound and free probe is indicated to the right of each gel. Asterisks indicate BC50s which are significantly different from CACACA (*p<0.05, **p<0.01), as calculated by a unpaired t-test between binding values determined from a minimum of three independent protein titrations.
Figure 3 Binding of hnRNP LL is more sensitive than hnRNP L to spacing of CA dinucleotides. (A) Complete sequence used for binding in panel B and as backbone for experiments in Figure 3 and 5. (B-F) Representative native gel analysis (EMSA) of purified, recombinant GST-tagged hnRNP L or Flag-tagged hnRNP LL incubated with radiolabeled T7-transcribed RNAs corresponding to a variant of the sequence in panel A. For each panel the sequence shown was substituted at the capitalized positions in panel A. CA dinucleotides are underlined, for panels C-F spacers between CAs are in red (N=spacer #). Affinities (Concentration of 50% binding = BC50) from at least three independent replicates of the EMSAs are shown below gels. Bound and free probe is indicated to the right of each gel. Asterisks indicate BC50s which are significantly different from CACACA (*p<0.05, **p<0.01), as calculated by a unpaired t-test between binding values determined from a minimum of three independent protein titrations.CC BY · PubMed Central
Figure 4 Complete RNAcompete data shows a hnRNP LL-specific preference for a two nucleotide spacer between CA dinucleotides. A bargraph for hnRNP L (A) and hnRNP LL (B) showing the mean Z-score for each possible spacing of 0 to 4 between two CA dinucleotides. Means were calculated for all 8-mers within the RNAcompete dataset that contain the sequence CA[N0-4]CA. Error bars show the standard error.
Figure 4 Complete RNAcompete data shows a hnRNP LL-specific preference for a two nucleotide spacer between CA dinucleotides. A bargraph for hnRNP L (A) and hnRNP LL (B) showing the mean Z-score for each possible spacing of 0 to 4 between two CA dinucleotides. Means were calculated for all 8-mers within the RNAcompete dataset that contain the sequence CA[N0-4]CA. Error bars show the standard error.CC BY · PubMed Central
Figure 5 A pyrimidine residue prior to the second CA is detrimental to the binding of both hnRNP L and hnRNP LL. (A-C) Representative native gel analysis (EMSA) of purified, recombinant GST-tagged hnRNP L or Flag-tagged hnRNP LL incubated with radiolabeled T7-transcribed RNAs corresponding to a variant of the sequence in panel 3A. For each panel the sequence shown was substituted at the capitalized positions in panel 3A. CA dinucleotides are underlined, spacers nucleotides between CAs are in red (all have a 2-nucleotide spacer). Affinities (Concentration of 50% binding = BC50) from at least three independent replicates of the EMSAs are shown below gels. Note panel 5A is the same construct as shown in 3B, duplicated to simplify comparison of binding. Bound and free probe is indicated to the right of each gel. Asterisks indicate BC50s which are significantly different from CACACA (** p<0.01), as calculated by a unpaired t-test between binding values determined from a minimum of three independent protein titrations.
Figure 5 A pyrimidine residue prior to the second CA is detrimental to the binding of both hnRNP L and hnRNP LL. (A-C) Representative native gel analysis (EMSA) of purified, recombinant GST-tagged hnRNP L or Flag-tagged hnRNP LL incubated with radiolabeled T7-transcribed RNAs corresponding to a variant of the sequence in panel 3A. For each panel the sequence shown was substituted at the capitalized positions in panel 3A. CA dinucleotides are underlined, spacers nucleotides between CAs are in red (all have a 2-nucleotide spacer). Affinities (Concentration of 50% binding = BC50) from at least three independent replicates of the EMSAs are shown below gels. Note panel 5A is the same construct as shown in 3B, duplicated to simplify comparison of binding. Bound and free probe is indicated to the right of each gel. Asterisks indicate BC50s which are significantly different from CACACA (** p<0.01), as calculated by a unpaired t-test between binding values determined from a minimum of three independent protein titrations.CC BY · PubMed Central
Figure 6 HnRNP L and hnRNP LL have different sensitivity to mutation of individual CA dinucleotides within the CD45 exon 4 ESS1 element. (A) Sequence of the ESS1 element from CD45 exon 4 with ARS element underlined, CA dinucleotides in bold and numbered consecutively, and segments that correspond to the above-described binding consensus for hnRNP L (L) or hnRNP LL (LL) are indicated in blue and grey respectively. (B) Binding curve for hnRNP L, as calculated from a minimum of three EMSAs, for the wildtype ESS1 or variants that are mutated at individual CAs (see panel D for legend). (C) Binding curve for hnRNP LL as described in panel B. (D) Legend for binding curves in panels B and C along with the apparent affinities for each RNA-protein combination as derived from the binding curves. Asterisks indicate affinities (concentration of 50% binding = BC50) which are significantly different from ESS (* p<0.05, ** p<0.01), as calculated by a unpaired t-test.
Figure 6 HnRNP L and hnRNP LL have different sensitivity to mutation of individual CA dinucleotides within the CD45 exon 4 ESS1 element. (A) Sequence of the ESS1 element from CD45 exon 4 with ARS element underlined, CA dinucleotides in bold and numbered consecutively, and segments that correspond to the above-described binding consensus for hnRNP L (L) or hnRNP LL (LL) are indicated in blue and grey respectively. (B) Binding curve for hnRNP L, as calculated from a minimum of three EMSAs, for the wildtype ESS1 or variants that are mutated at individual CAs (see panel D for legend). (C) Binding curve for hnRNP LL as described in panel B. (D) Legend for binding curves in panels B and C along with the apparent affinities for each RNA-protein combination as derived from the binding curves. Asterisks indicate affinities (concentration of 50% binding = BC50) which are significantly different from ESS (* p<0.05, ** p<0.01), as calculated by a unpaired t-test.CC BY · PubMed Central

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Research works printed but not linked: 13

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Metadata

Authors
Smith, S. A., Ray, D., Cook, K. B., Mallory, M. J., Hughes, T. R., & Lynch, K. W.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-11-11
Volume
8
Issue
11
Pages
e80701
ISSN
1932-6203
DOI
10.1371/journal.pone.0080701
PMC
PMC3823766
Cited by
40
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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Smith, S. A., Ray, D., Cook, K. B., Mallory, M. J., Hughes, T. R., & Lynch, K. W. (2013). Paralogs hnRNP L and hnRNP LL Exhibit Overlapping but Distinct RNA Binding Constraints. PLoS ONE. https://doi.org/10.1371/journal.pone.0080701