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FC0071
Leucine-rich repeat-containing protein 16A (LRRC16A)
- Actin capping protein (CP)
Biological function
The capping protein (CP) ARp2/3 myosin I linker (CARMIL) is a multifunctional actin regulator.
Domain organization/sequence features
The N-terminal domain of CARMIL includes leucine-rich repeats.
Structural evidence
The binding position for the CPI motif is distant to the actin binding interface. The structure reveals two ordered CARMIL
regions: the CPI motif, Ile971–Cys1004, and Arg1021–Thr1035, which binds to the under-side of the CP mushroom cap on the
opposite side of the CP mushroom stalk to which the CPI motif binds. This region appears not to be present in other CPI-motif
proteins from sequence analyses and is termed the CARMIL-specific interaction (CSI) motif. The linker between the two
ordered region is disordered in the sequence. The extended nature of the CARMIL CPI and CSI motifs leads to multiple
interactions with CP. The disordered residues between the CPI and CSI motifs may be sufficient in length to reach toward the
actin binding site on the topside of the CP mushroom cap.
Biochemical evidence
The minimal peptide, which shows both CP sequestration and uncapping activities and is referred to henceforth as the CP
interaction (CPI) motif. The construct containing peptide sequences, which flank the CPI motif, leading to stronger uncapping
activity. The CPI motif from CARMIL (971-1004) binds CP (Kd ~ 0.1–0.2 μM), while the larger, 964-1078 segment
has KD ~ 1.5 nM and higher uncapping and sequestration activities.
Structure/Mechanism
It has been concluded that the C-terminal flanking region of the CP motif is required for high-affinity interactions, mostly due to
the electrostatic interactions established between the acidic residues of CP and the basic residues of the CARMIL.
Mechanism category
tethering, flexibility modulation
Significance
Fuzzy regions serve as allosteric modulators to suppress conformational dynamics of CP and restrict to low-affinity filament
bound conformation. Capping activity of CP is fine- tuned for the highly orchestrated assembly of the cellular actin machinery,
and the conformational flexibility of CP provides the structural basis for the regulation.
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