Large tilts in transmembrane helices can be induced during tertiary structure formation

Area of Science:

• Structural Biology
• Membrane Protein Biophysics
• Protein Folding Dynamics

Background:

• Early models assumed transmembrane helices (TMHs) were perpendicular to membranes.
• High-resolution structures reveal significant TMH tilt angles are common.
• The origin of TMH tilt (intrinsic vs. induced) remains unclear.

Purpose of the Study:

• To investigate whether TMH tilt is an inherent property or acquired during protein folding.
• To determine the factors influencing TMH orientation within integral membrane proteins.

Main Methods:

• Utilized a glycosylation mapping technique.
• Inserted individual TMHs into the membrane to assess their intrinsic properties.
• Compared membrane-embedded segment lengths of isolated helices versus those in multi-spanning proteins.

Main Results:

• Four highly tilted TMHs exhibited significantly shorter membrane-embedded segments when inserted alone.
• This contrasts with their observed lengths in high-resolution structures of multi-spanning proteins.
• The data indicate that isolated helices do not intrinsically adopt the observed tilted conformations.

Conclusions:

• TMH tilt is not an intrinsic property of the helix itself.
• Tertiary packing interactions during protein folding induce helix tilting.
• Helix tilting occurs subsequent to the initial membrane insertion event.