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mRNA Splicing

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Spliceosomes



Pre-mRNA Splicing


Spliceosomes 1

Spliceosomes: General
  • Location: Nucleus
  • Function
    • Process pre-mRNA by splicing out intronic nucleic acids
    • Producing mRNA which is then translated to protein in ribosomes
  • Mechanisms of action
    • Recognition of the intron/exon boundaries
      • Via splice sequences & multiple other weak signals
    • Catalysis of cut-and-paste reactions that remove introns and join exons
  • Contents
snRNP components
  • Namesake snRNA (e.g. U1 snRNP has U1 snRNA)
    • snRNP RNAs: U1 ; U2 ; U4; U5; U6
    • Differ from mRNAs in cap structure: 2,2,7-trimethyl guanosine
  • "Smith" (SM) core proteins common to all snRNPs
    • B & B' , D1 , D2 , D3 , E , F, G
    • Bind AU4-6G sequence
    • Bind snRNA first
    • Targets of autoantibodies (anti-Sm) in systemic lupus
      • Major targets: Sm-B/B' and D proteins
      • Antibodies precipitate U1, U2, U4/U6 & U5 particles
  • snRNP-specific proteins
    • U1: 70k , A , C
      • Target of selective autoantibodies (anti-nRNP)
        • In mixed connective tissue disease
      • Protein target usually U1-70k or U1A
    • U2: A' , B''
    • U5: 25K, 1BP
  • Brain specific: SNRNP-N
  • Other
Functional roles for each snRNP
  • U1
    • Initially bound to 5'-splice site
    • Released on recruitment of U4/U5/U6
      • ? Determines which 5'-splice site is used
  • U2
    • Initially binds branchpoint recognition sequence
    • Forms two duplexes with U6
      • Brings intron 5'-splice site close to the branchpoint
  • U4
    • Initially complexed with U5 and U6
    • Keeps U6 in an unfolded conformation
    • Released after delivering U6 to the 5'-splice site
      • ? U6 chaperone
  • U5
    • Initially complexed with U4 and U6
    • Binds exon sequences
      • Location
        • Upstream of 5'-splice site
        • Downstream of 3'-splice site
      • ? Guide sequence for holding exons together
  • U6
    • Initially complexed with U4 and U5
    • Displaces U1 from 5'-splice site
    • Forms duplex with intron sequences
    • Complexes with U2
      • Brings intron 5'-splice site close to branchpoint
      • ? Catalytic activity
Spliceosomes: Illustrations

Pre-mRNA splicing






U1 binds to 5' splice site




U2 binds to branchpoint
recognition sequence





U4-U5-U6 complex
binds to 5' splice site




 
U1 is displaced
U6 binds to U2
5'-splice site near branchpoint




 
U5 binds exon sequences
Intron is removed



   


Pre-mRNA splicing: Human disorders2

Mutation effects: General principles Mutation effects: Disorders


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Return to Muscle autoantibodies

References
1. Clin Exp Rheum 1997;15:549-560
2. Genes & Devel 2003;17:419437

6/12/2016