Key result
Cryo-EM reveals a partially disordered ARPC5L N-terminal half enhances actin nucleation activity versus ARPC5.
Why the study?
Mammalian Arp2/3 complexes contain isoforms that produce complexes with different properties, but how isoform diversification affects Arp2/3 function is unclear.
The study reveals that the N-terminal region of ARPC5/ARPC5L isoforms determines the actin nucleation activity of the Arp2/3 complex.
ARPC5L disorder boosts Arp2/3 nucleation; leaves open isoform-specific roles in cardiac cytoskeletal regulation.
The Arp2/3 complex regulates many cellular processes by stimulating formation of branched actin filament networks. Because three of its seven subunits exist as two different isoforms, mammals produce a family of Arp2/3 complexes with different properties that may be suited to different physiological contexts. To shed light on how isoform diversification affects Arp2/3 function, we determined a 4.2 Å resolution cryo-EM structure of the most active human Arp2/3 complex containing ARPC1B and ARPC5L, and compared it with the structure of the least active ARPC1A-ARPC5-containing complex. The architecture of each isoform-specified Arp2/3 is the same. Strikingly, however, the N-terminal half of ARPC5L is partially disordered compared to ARPC5, suggesting that this region of ARPC5/ARPC5L is an important determinant of complex activity. Confirming this idea, the nucleation activity of Arp2/3 complexes containing hybrid ARPC5/ARPC5L subunits is higher when the ARPC5L N-terminus is present, thereby explaining activity differences between the different Arp2/3 complexes.
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Loeffelholz et al. (2020) studied this question. ARPC5L isoform vs. ARPC5 isoform was evaluated on Actin nucleation activity and structural conformation. The cryo-EM structure of the human Arp2/3 complex reveals that the N-terminal half of ARPC5L is partially disordered compared to ARPC5, which enhances actin nucleation activity.
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