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Revision as of 00:46, 3 April 2018

HRP1 found in Saccharomyces cerevisiae

Figure Legend

Function

Disease

Relevance

Overall Structural highlights

HRP1 is made up of two RNA binding domains (RBDs) that contain residues serving to facilitate RNA recognition. These two domains fold into a βαββαβ secondary structure^[1] in an RNA-free environment, allowing Hrp1 to behave rigidly (source). The includes residues extending from Ser158 to Ala233 and the from Lys244 to Ala318. Both RBDs are composed of a four-stranded beta-sheet with two alpha helices spanning across one side of the sheet. The linker region is made up of Ile234 to Gly243. When RNA is introduced into the environment, conformational change is demonstrated within the linker region and a forms from Arg236 to Lys241. The helix that forms is made up of many charged polar residues that stabilize themselves through between Arg236-Asp240 and Asp237-Lys241.^[2]

Hrp1 identifies the polyadenylation enhancement element (PEE) in the 3' UTR of RNA through Van Der Waals interactions and Hydrogen bonding. The PEE is made up of UAUAUA sequence in which HRP1 recognizes and binds. The association of these RBD domains aids in binding through the development of a deep highly positively charged cleft between the two. This cleft is v-shaped, accommodating the RNA very well. Some RNA bases have been revealed to be buried within protein pockets while some are observed in between protein loops. The recognition of RNA by Hrp1 is entirely dominated by RNA-protein interactions. The absence of RNA base pairing or RNA base-base stacking which have been observed in similar complexes (***) might explain the ability of Hrp1 to target short RNA sequences in comparison to those recognized by similar proteins.

Recognition Specificity

HRP1 is able to discriminate RNA from DNA due to ribose-specific hydrogen bonds, such as the ones found between the 2’OH of Ade2 and phosphate oxygen of Ura3, and between the 2’OH of Ade6 and 5’O of Ura7. Furthermore, the residues found in the binding site of HRP1 have specific interactions with each individual base of the 5’-AUAUAU’3’ RNA sequence. The adenines are deeply buried in hydrophobic pockets, and uracil recognition is mainly dependent on Van der Waals interactions.

Adenosine recognition

HRP1 specifically binds 3 Adenosine ribonucleotides within the PEE. Adenosine recognition is facilitated through the use of hydrophobic pockets found within HRP1. Ade2 binding is made possible through the interaction of Phe246, which makes up the foundation of the recognition pocket. In addition, the C-terminal of Arg321 interacts with the opposite side of Ade2 through pi-cation interactions. Upon binding, Ade4 is fit inside of a deep hydrophobic pocket made up of Trp168 and Lys226. The stacking of Trp in this interaction is demonstrated as a unique feature of Hrp1; similar Hrp1-like proteins maintain this conserved Trp, but do not demonstrate Trp stacking. The hydrophobic pocket in which Ade6 resides upon binding is made up of Phe162 and Ile234, which sandwich Ade6. In addition, the three Adenosines participating in binding are also recognized by Hydrogen bonds to bases that determine specificity. The three Adenosines recognized display 1, 3, and 2 Hydrogen Bond(s), respectively. The three backbone amides (Glu319 NH, Trp168 NH, Ile234 NH) hydrogen bond with nitrogen atoms of the three adenosine bases (Ade2 N1, Ade4 N7, Ade6 N1). In addition, Ade4 makes base specific contacts with Asn167 and Lys226. Ade4 acts as the donor in it’s interaction with Lys226 and as the acceptor with Asn167. Ade6 interacts with Arg232 in which it acts as the donor.

Uracil recognition

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References

^{[3] [4]}

1. ↑ .
2. ↑ .
3. ↑ Clery, Antoine, et al. “RNA Recognition Motifs: Boring? Not Quite.” Current Opinion in Structural Biology, Elsevier Current Trends, 30 May 2008, www.sciencedirect.com/science/article/pii/S0959440X08000584.
4. ↑ Perez-Canadillas, Jose Manuel. “Grabbing the Message: Structural Basis of MRNA 3′UTR Recognition by Hrp1.” The EMBO Journal, vol. 25, no. 13, 2006, pp. 3167–3178., doi:10.1038/sj.emboj.7601190.