User:Dzmitry Mukha/sandbox1

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hnRNP A1

hnRNP A1 (alternative or associated names: HNRPA1, ALS19, ALS20, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins, and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.

1 hnRNP A1
2 Structure overview
3 Medical implications
4 Structures
- 4.1 X-ray
- 4.2 Solution NMR
5 References

Structure overview

Introduction

Human hnRNP A1 consists of 320 amino acids. is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of (2H4M). and (together span residues 1 to 196) form . A 38-amino acid sequence at C-terminus is necessary for nuclear localization of hnRNP A1. RGG tripeptides in disordered C-terminal parts can also bind RNA.

The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.

The structure of the protein first was studied by means of NMR in 1994^[1]. To date, several crystal structures of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments ^[2]^[3]^[4]^[5]^[6]. NMR structure of hnRNP A1 RRM domains, which is available in PDB, was determined using a segmental labeling strategy^[7].

Natural variants and isoforms

Few natural variants of hnRNP A1 were found. Substitution (rs6533) was reported, but it has an unknown impact on the protein function. ALS20 variant carries two substitutions, D314N and N319S, in the C-terminal region.

The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do not affect RNA-binding part called UP1. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for the prion-like aggregation of hnRNP A1.

Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated^[8].

Interaction between RRM domains

RRM1 and RRM2 domains have opposite orientations in the UP1 structure, and an approximate twofold symmetry can relate them. Two RRMs are interaction with one another via two Arg-Asp salt bridges. , whereas has both charge interaction and a hydrogen bond with . In addition, these four amino acids interact with two water molecules stabilizing inter-domain contacts. The interactions between domains of UP1 is considered as quite weak since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.

Nucleic acid binding

In each RRM domain, there are two , β1 and β3. While the UP1 part of hnRNP A1 has a calculated isoelectric point of 8.3, electric charges are not evenly distributed on the protein surface. The β -sheet side of the protein surface is more positively charged than the α-helix side. Two conserved phenylalanines ( in RRM1, and F108 and F150 in RRM2) are among the most important residues for nucleic acid binding. They participate in aromatic ring stacking with nucleic acid bases. in RRM1 and (F148 in RRM2) can bind nucleic acid backbone atoms via van der Waals contacts. In addition, there are that clearly interact with nucleic acid: R55 in RRM1 (R146 in RRM2), and two charged residues located in β4 (E85 and K87 in RRM1, E176 and R178 in RRM2).

Medical implications

Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives the development of amyotrophic lateral sclerosis. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.^[9]. hnRNP A1, together with septin 6, facilitate hepatitis C virus replication^[10].

Structures

X-ray

Solution NMR

2lyv

References

↑ Garrett DS, Lodi PJ, Shamoo Y, Williams KR, Clore GM, Gronenborn AM. Determination of the secondary structure and folding topology of an RNA binding domain of mammalian hnRNP A1 protein using three-dimensional heteronuclear magnetic resonance spectroscopy. Biochemistry. 1994 Mar 15;33(10):2852-8. PMID:8130198
↑ Xu RM, Jokhan L, Cheng X, Mayeda A, Krainer AR. Crystal structure of human UP1, the domain of hnRNP A1 that contains two RNA-recognition motifs. Structure. 1997 Apr 15;5(4):559-70. PMID:9115444
↑ Vitali J, Ding J, Jiang J, Zhang Y, Krainer AR, Xu RM. Correlated alternative side chain conformations in the RNA-recognition motif of heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 2002 Apr 1;30(7):1531-8. PMID:11917013
↑ Ding J, Hayashi MK, Zhang Y, Manche L, Krainer AR, Xu RM. Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA. Genes Dev. 1999 May 1;13(9):1102-15. PMID:10323862
↑ Myers JC, Moore SA, Shamoo Y. Structure-based incorporation of 6-methyl-8-(2-deoxy-beta-ribofuranosyl)isoxanthopteridine into the human telomeric repeat DNA as a probe for UP1 binding and destabilization of G-tetrad structures. J Biol Chem. 2003 Oct 24;278(43):42300-6. Epub 2003 Aug 6. PMID:12904298 doi:http://dx.doi.org/10.1074/jbc.M306147200
↑ Myers JC, Shamoo Y. Human UP1 as a model for understanding purine recognition in the family of proteins containing the RNA recognition motif (RRM). J Mol Biol. 2004 Sep 17;342(3):743-56. PMID:15342234 doi:10.1016/j.jmb.2004.07.029
↑ Barraud P, Allain FH. Solution structure of the two RNA recognition motifs of hnRNP A1 using segmental isotope labeling: how the relative orientation between RRMs influences the nucleic acid binding topology. J Biomol NMR. 2012 Dec 18. PMID:23247503 doi:http://dx.doi.org/10.1007/s10858-012-9696-4
↑ Li T, Evdokimov E, Shen RF, Chao CC, Tekle E, Wang T, Stadtman ER, Yang DC, Chock PB. Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: a proteomic analysis. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8551-6. Epub 2004 May 25. PMID:15161980 doi:http://dx.doi.org/10.1073/pnas.0402889101
↑ Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013 Mar 28;495(7442):467-73. doi: 10.1038/nature11922. Epub 2013 Mar 3. PMID:23455423 doi:http://dx.doi.org/10.1038/nature11922
↑ Kim CS, Seol SK, Song OK, Park JH, Jang SK. An RNA-binding protein, hnRNP A1, and a scaffold protein, septin 6, facilitate hepatitis C virus replication. J Virol. 2007 Apr;81(8):3852-65. Epub 2007 Jan 17. PMID:17229681 doi:http://dx.doi.org/10.1128/JVI.01311-06

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