A link between sequence conservation and domain motion within the AAA+ family

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• AAA+ proteins are vital molecular chaperones involved in protein complex assembly/disassembly across all life forms.
• Structural studies reveal conserved elements in AAA+ proteins, suggesting a link between nucleotide binding and mechanical force generation.
• The general properties of nucleotide-induced conformational changes in the AAA+ protein family remain unclear.

Purpose of the Study:

• To investigate sequence conservation within the AAA+ protein family.
• To identify distinct subfamilies based on conserved linker sequences.
• To explore the relationship between linker sequences and nucleotide-induced conformational changes using molecular dynamics simulations.

Main Methods:

• Sequence conservation analysis within the AAA+ protein family.
• Identification of conserved linker sequences defining distinct subfamilies.
• Molecular dynamics (MD) simulations of AAA+ protein X-ray structures from identified subfamilies.

Main Results:

• Two distinct AAA+ subfamilies were identified, each characterized by a unique conserved linker sequence.
• MD simulations revealed differences in N-linker peptide dynamics, subdomain motion, and quaternary structure cooperativity between subfamilies.
• Extrapolation of subdomain movements from MD simulations accurately predicted structures consistent with cryo-electron microscopy (cryo-EM) data.

Conclusions:

• Conserved linker sequences in AAA+ proteins are critical for transmitting conformational changes upon nucleotide binding/hydrolysis.
• Subfamily-specific linker sequences influence subdomain motion and inter-domain communication, affecting mechanical force generation.
• MD simulations coupled with structural data provide a powerful approach to understanding AAA+ protein conformational dynamics and function.