View source for 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.  

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== Structure overview ==
<StructureSection load='2UP1' size='350' side='right' caption='Human hnRNP A1 structure complex with DNA (PDB code [[2up1]])' scene='70/701439/Na_binding_1/1'>
=== Introduction ===
__NOTOC__
Human hnRNP A1 consists of 320 amino acids. The <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> 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 the C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>. These two domains are arranged in antiparallel orientation facilitating binding with bent RNA strand.

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<ref>PMID 8130198</ref>. To date, several [[#Structures|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains, which is available in PDB, was determined using a segmental labeling strategy<ref>PMID 23247503</ref>.

=== Natural variants and isoforms ===

Few natural variants of hnRNP A1 were found. Substitution 
<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has an unknown impact on the protein function. [http://omim.org/entry/615426 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<ref>PMID 15161980</ref>.

=== 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. <scene name='70/701439/Na_binding_1_sb1/1'>R75 interacts with D155</scene>, whereas <scene name='70/701439/Na_binding_1_sb2/1'>R88</scene> has both charge interaction and a hydrogen bond with <scene name='70/701439/Na_binding_1_sb2/1'>D157</scene>. 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 ===

Each RRM domain contains two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, 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 (<scene name='70/701439/Na_binding_1_phe_na/1'>F17 and F59</scene> 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. <scene name='70/701439/Na_binding_1_phe_na/2'>F57</scene> in RRM1 and (F148 in RRM2) can bind nucleic acid backbone atoms via van der Waals contacts. In addition, there are <scene name='70/701439/Na_binding_1_phe_na/3'>three charged residues</scene> 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).

</StructureSection>

== Medical implications ==

=== Aggregation of hnRNP A1 leads to proteinopathies ===

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 [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is also caused by a heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>. 

=== hnRNP A1 regulates isoform content of a major component of myelin ===

Myelin-associated glycoprotein (MAG) is a major component of myelin in vertebrates. ''Mag'' gene produces two alternative isoforms: short S-MAG with exon 12 containing termination codon and L-MAG without exon 12. L-MAG is common for the central nervous system. It was shown that the sequence UAGGU is enriched in the region of ''Mag'' exon 12, and this sequence in a proper secondary RNA structure is responsible for interaction with hnRNP A1 <ref>PMID 23704325</ref>. 

=== HIV-1 recruits hnRNP A1  ===

Human immunodeficiency virus 1 (HIV-1) uses alternative splicing during its life cycle, generating more than 40 spliced isoforms. It is considered that hnRNP A1 competes with another human RNA-binding protein, [[SR | SR]], for binding with viral splicing regulatory elements. For conserved HIV-1 ESS3 stem loop structure, it was confirmed that hnRNP A1 binds with purines tighter than to pyrimidines (binding with AG dinucleotide is shown in [[HnRNP_A1#Nucleic_acid_binding|Nucleic acid binding]] section)<ref>PMID 24628426</ref>.  

=== Enterovirus 71 needs hnRNP A1 for translation ===
Enterovirus 71 (EV71) us a positive sense, single-stranded RNA virus that is a member of ''Picornaviridae'' family. Infections proceeds via a cytoplasmic replication cycle. Translation of viral proteins is initiated by a type I internal ribosomal entry site (IRES) located within the 5-non-coding region. To use IRES initiation, EV71 recruits host hnRNP A1 protein forcing redistribution of this protein from the nucleus to the cytoplasm.  
<ref>PMID 23727900</ref>

=== Other viruses ===
hnRNP A1, along with septin 6, facilitates hepatitis C virus replication<ref>PMID 17229681</ref>. 

== 3D Structures ==

See [[Nucleoprotein]]

== References ==
<references/>

[[Category:Transcription|Transcription]]
[[Category:Rna processing |RNA Processing]]