MEMBRANE SHAPING AND REMODELING BY PROTEINS

THANKS AND CREDIT:

FELIX CAMPELO

HARVEY MCMAHONADI PICK

TEL AVIV GROUP: COLLABORATION:

TOM SHEMESH LEONID CHERNOMORDIK

WINFRIED WEISSENHORNGUR FABRIKANT

TOM RAPOPORT

h/R~ 0.2

Radius of curvature R ~ 20 nm is close to the monolayer thickness h ~ 4 nm

INTRACELLULAR MEMBRANE SHAPES AND DYNAMICS

VIRAL MEMBRANE DYNAMICS

THREE ESSENTIALLY DIFFERENT GEOMETRICAL TRANSFORMATIONSMEDIATING DYNAMIC SHAPING

BENDING (GENERATION OF CURVATURE) REMODELING BY FISSION OR FUSION (CHANGE OF MEMBRANE CONTINUITY,

AND MEMBRANE TOPOLOGY)

FISSION

FUSION

MEMBRANES RESISTS TO BOTH BENDING AND REMODELING

MEANING THAT

ENERGY HAS TO BE SUPPLIED BY SPECIAL PROTEINS

MEMBRANE RESISTENCE TO MEAN CURVATURE GENERATION:INVOLVED IN SHAPING AND REMODELING

POSITIVE CURVATURE NEGATIVE CURVATURE

BENDING STRESS

22

1scc JJw

BENDING ENERGY: HELFRICH MODEL

sc JJ

c BENDING (SPLAY) MODULUS

SPONTANEOUS CURVATURE

Tkerg Bc 10104 13

SJ

ENERGY OF GAUSSIAN CURVATURE (HELFRICH MODEL)

CHANGE OF MEMBRANE CONNECTIVITY (TOPOLOGY): INVOLVED IN REMODELNG

)1(4 pF

CONSIDERABLE ENERGY IS ASSOCIATED WITH THE FISSION EVENT

TkB5MODULUS OF GAUSSIAN CURVATURE

IN ADDITION, TRANSIENT MEMBRANE DISCONTINUITY REQUIRES ENERGY

)1(4 pdAwF K KwK

QUESTIONS TO ANSWER:

PHYSICS:MECHANISTIC PRINCIPLES OF MEMBRANE BENDING AND FUSION/FISSIONBY DIFFERENT PROTEINS BASED ON ENERGY CALCULATIONS.

BIOLOGY:WHETHER THESE PRINCIPLES ARE UNIVERSAL AND DETERMINE ACTION OF DIVERSEPROTEINS

BIOLOGY:WHETHER SAME PROTEINS CAN DRIVE BOTH FUSION AND FISSION

BIOLOGY:WHETHER SAME PROTEINS CAN BE USED TO DRIVE MEMBRANE BENDING AND REMODELING OR DIFFERENT PROTEINS ARE NEEDED

CURVATURE GENERATION BY LIPIDS

EFFICTIVE NON-BILAYER SHAPES OFLIPID MOLECULES

ASYMMETRY OF TWO MONOLAYERS:a. DIFFERENT NUMBERS OF LIPID MOLECULESb. DIFFERENT LIPID COMPOSITIONS

FOR BILAYER

ASYMMETRICAL STRUCTURE OF LIPID MOLECULES

FOR MONOLAYER

SPONTANEOUS CURVATURES OF REPRESENTATIVE LIPIDS(RAND AND FULLER)

X-rays measurements of lipid mesophases

P Rand (Brock Univ., Canada)

0sJLysophosphatidylcholine (LPC): 126.0

8.3

1 nmnm

J LPCs

Common Lipids:

Phosphatidylcholine (PC): 111.07.8

1 nmnm

J PCs

Lysolipids:

Hexagonal lipids

0sJ

0sJDioleoylPE (DOPE)

135.08.2

1 nmnm

J DOPEs

Diacylglycerol (DAG) 191.01.1

1 nmnm

J DOPEs

MECHANISMS OF MEMBRANE CURVATURE GENERATION BY DIRECT ACTION OF PROTEINS

HYDROPHOBIC INSERTION SCAFFOLDING

CAMPELO ET AL 2008 VOTH ET AL 2008

SYNAPTOTAGMIN(D.Z.HERRICK ET AL., 2006)

FUSION PEPTIDES

AMPHIPATHIC HELICES C2 DOMAINS

L. TAMM, BBA 2007

HYDROPHOBIC-INSERTION MECHANISM OF MEMBRANE BENDING

N-BAR DOMAINS N-BAR DOMAINS

SMALL G-PROTEINS

STRUCTURE

MODEL OF ACTION

HYDROPHOBIC INSERTION PROTEINS: EPSIN

TUBULATION OF PIP2 BILAYERS

D=20nm

SCAFFOLDING PROTEINS: BAR DOMAIN PROTEINS

EndophilinBAR

N-BAR

STRUCTURE MODEL OF ACTION

TUBULATION OF PS BILAYERS

D=20nm

STRUCTURE EHD2

MODEL OF ACTION

TUBULATION IN VIVO BY OVEREXPRESSION

OTHER TYPE OF SCAFFOLDING PROTEINS. EPSIN HOMOLOGY DOMAINS (EHD@)

TUBULATION OF PS BILAYERS

D=20nm

SMALL INCLUSION GENERATES ELASTIC DEFORMATION OF THE MONOLAYER MATRIX

SMALL HYDROPHOBIC INSERTION MECHANISM: QUALITATIVELY

MEMBRANE AS A THICK LAYER: RELEVANT SCALES ARE COMPARABLE WITH MEMBRANE THICKNESS

INTRA-MEMBRANE DISTRIBUTION OF STRESSES AND RIGITIES

from Illya, Lipowsky and Shillcock, J Chem Phys 122, 244901 (2005)σ

TRANS-MEMBRANE STRESS PROFILE

TRANS-MEMBRANE ELASTICITY PROFILE

λT

STRETCHING TRANSVERSE SHEAR

λS

dVuuudF lmikiklmikik )2

1(

λT λS

λ

COMPUTING MEMBRANE BENDING BY INSERTIONS

BEFORE INSERTIONDEFORMED STATE AFTER INSERTION

LOOKING FOR CONFORMATION OF MINIMAL ELASTIC ENERGY

FELIX CAMPELO

EFFECTIVE SPONTANEOUS CURVATURE OF INSERTION

Zinc/hMAXIMAL SPONT.CURV. FOR INCLUSION

ζinch ~ 0.75

MAXIMAL SPONT.CURV. FOR LIPID (LPC)

ζLPCh ~ 0.3

EFFECTIVE SPONTANEOUS CURVATURE OF INSERTION

0.05zinch

MEMBRANE TUBULATION BY N-BAR DOMAIN

SHALLOW HYDROPHOBIC INSERTIONS ARE MORE EFFECTIVE THEN LIPIDS

IN CURVATURE GENERATION

CURVATURE GENERATION BY SCAFFOLDING PROTEINS:

SHAPING OF ENDOPLASMIC RETICULUM