|
|
| 1855 |
C. Naegeli and C. Cramer describe
cell membrane as barrier essential to explain osmosis in plant
cells |
| 1859 |
Charles Darwin publishes his 'Origin
of Species' on his theory of evolution by natural selection |
| 1865 |
Gregor Mendel publishes his findings
on 'plant hybridization' laying out for the first time the mathematics
of genetic inheritance of independent factors |
| 1871, 1888 |
Hugo de Vries describes cell membrane
permeability for ammonia and glycerol |
|
|
| 1888 |
Walther
Nernst develops a theory of electrical potentials based
on diffusion of ions in solution. This theory (called Nernst
potential) became and still is fundamental in modeling ion flux
across biological membranes in electrophysiology |
| 1895-99 |
Ernest Overton develops the following
theories
- lipoid membrane enclosing animal and plant cells
- lipid-water partition theory for general anesthetic
action (alcohol narcosis)
- exchange of external Na for internal K ions
- proposed active transport (uphill) requiring
metabolic energy |
| 1905 |
R. Hoeber demonstrates the effect
of electrolytes (salt solutions) on the resting potential of
frog muscles |
| 1925 |
Gorter and Grendel propose lipid
bilayer structure for cell membranes; surface area covered by
lipids extracted from red blood cells on water surface is twice
as large as original surface of red blood cells.
The electrical capacitance
of cell membranes is used to estimate the thickness membranes
to be 33 Å; this value is in complete agreement with
modern data
|
| 1926, 1930 |
First accounts that proteins convey
enzymatic activity (urease, pepsin) in cellular metabolism;
an important step to demonstrate that proteins catalyze chemical
reactions and are not only structural components of cells |
| 1934 |
First successful X-ray study of
the globular protein pepsin by Bernal and Crowfoot; it does
not show high resolution details, but demonstrates water covered
protein surface |
| 1935 |
Danielli and Davson's membrane model
of globular proteins on surface of lipid bilayer; this model
specifically excludes transmembrane proteins based on the previously
shown hydrophilic surface of globular proteins |
| 1937 |
Citric Acid Cycle described by Hans
Krebs; this is the central energy yielding pathway in all
organisms; complete biochemical pathway reactions could be elucidated
in the absence of any protein structure information (kinetic
data represents macroscopic behavior of enzymes)
First demonstration by A.L.
Hodgkin for electrical transmission in nerve cells
|
| 1939 |
Glycolysis completely described
and enzymatic reactions demonstrated in vitro; although the
first third of the glycolytic pathway has been described in
the early 30s, the complete description has been obtained only
by 1939; however, the entire pathway has been reconstituted
in vitro using purified enzymes
Hodgkin together with A.F.
Huxley publish the first action potentials recorded from
inside a nerve fiber
|
| 1941 |
'One gene, one enzyme' hypothesis
by Beadle
and Tatum |
| 1942 |
First demonstration of ion selectivity
on enzymes; K+ ions stimulate pyruvate kinase, but Na+
ions do not; the property of proteins to discriminate among
substrates based on charge, size and structure is essential
for all membrane transport processes |
| 1944 |
DNA is carrier of genetic information
in bacteria (Oswald Avery) |
| 1945 |
First complete amino acid content
of a protein is published (not its sequence, however)
Voltage clamp technique developed to study
macroscopic ion currents in neurons; Hodgkin and Huxley publish
resting and action potential recordings form single nerve
fibers
|
| 1949 |
Mitochondria are shown to be organelles
responsible for oxidative phosphorylation and containing
enzymes of Krebs cycle (Lehninger) |
| 1951 |
First complete amino acid sequence
published of the protein hormone insulin by Fred
Sanger
Proposed model for alpha helix and beta sheet
and importance of so called hydrogen bonds in protein structures
(Pauling
and Corey)
|
| 1952 |
First high resolution electron micrograph
of biological membranes of mitochondria, by G.
Palade |
| 1953 |
DNA structure at atomic resolution
by Crick,
Watson, and Wilkins; they propose a model for DNA replication
based on the structural information; the concept of structure-function
relationship has been successfully used to solve a major problem
in biology |
| 1958 |
Induced-fit model of substrate protein
interaction proposed by Daniel Koshland addressing the importance
of structural flexibility of proteins for their function |
| 1961 |
Chemiosmotic theory by Peter
Mitchell postulating a proton gradient as energy source
for ATP synthesis in mitochondria |
| 1962 |
High resolution structure of myoglobin
at 2 Angstrom confirms for the first time the existence of alpha
helix structures in proteins (Perutz
and Kendrew)
Black lipid membrane; successful formation
of the first artificial lipid bilayer (Mueller and Rudin)
mimicking cell membranes
Kauzman and Tanford develop theory on hydrophobic
effect on protein folding and stability, an important concept
to understand cell membrane assembly and stability
The structure of the enzyme lysozyme with a
bound inhibitor molecule solved at 2 Angstrom resolution giving
the first structural insight into enzyme-substrate interaction
and Koshland's induced fit theory
|
| 1963 |
Genetic code solved; links
DNA sequence to amino acid sequence in proteins (Holley,
Khorana, Nirenberg)
Allosteric mechanism described by J.Monod,
F. Jacob, and Changeux to explain regulation and cooperativity
in enzymes by ligands that bind to a protein on a location
different from the active site; mechanistically induced-fit
and allosterism are closely related phenomena
|
| 1965 |
Multilamellar vesicles in vitro
separating aqueous compartments; because they contain multiple
membrane layers, they are not suitable for transport studies |
| 1969 |
Unilamellar lipid vesicles used
for membrane protein reconstitution to study ion flux (Huang);
this single membrane vesicles revolutionize transport studies
because they can be prepared in large quantities; the kinetics
of many channels, pumps and transporters has been demonstrated
using these membrane system without having to know their structure; |
| 1970 |
Experimental evidence that membrane
proteins can diffuse laterally in cell membranes (Frye and Edidin)
Unit channel structure for Gramicidin A peptide
confirmed by Hladky and Haydon using black lipid membranes
by demonstrating "the discreteness of conduction change in
planar membranes in the presence of certain antibiotics"
|
| 1972 |
Singer and Nicolson propose the
fluid-mosaic model of cell membranes replacing the model of
Danielli and Davson from 1935; the new model explicitly postulates
integral membrane proteins
Monolayer derived planar bilayers making synthetic
membranes virtually solvent free (Montal and Mueller) to study
intrinsic properties of ion channels; the importance of this
technical advance lies in the fact that it can be used to
mimic the lipid composition and distribution of cell membranes
which affects the activity of proteins
... ... ... read more
|
| 1975 |
Glycophorin, first integral membrane
protein sequenced
First electron microscopy derived structure
of a membrane protein, bacteriorhodopsin at 7 Angstrom resolution
(Henderson and Unwin); structure shows seven transmembrane alpha
helices supporting the idea that alpha helices but not beta
sheets are the secondary structure of choice for membrane proteins;
this idea strongly influences research on structure-function
relationship of membrane protein; beta barrel models for bacterial
porin and beta helix structure of Gramicidin are dismissed as
exceptions confirming the rule |
| 1976 |
Patch-clamp technique developed
by Neher
and Sakmann; this modification of the voltage clamp setup
developed in the 1940s allows for the first time the measurement
of single channel activity in living cells instead of the usual
macroscopic currents; the existence of separate ion channels
selective for either Na, K or Ca ions can be demonstrated at
the single channel level |
| 1979 |
Vesicle supported planar bilayers
making synthetic membranes completely solvent free (H. Schindler);
initially used to study purified nicotinic acetylcholine receptor
and bacterial porins |
| 1980 |
First membrane protein crystal of
bacterial porin diffracts to high resolution, phase problem,
and thus structure, not solved (Garavito and Rosenbusch);
electron microscopy and circular dichroism have by now firmly
established the exclusive beta sheet composition of this pore
protein. The so called beta barrel structure is proposed
and later found to be a widely used structural feature in many
proteins |
| 1985 |
First X-ray high resolution structure
of a membrane protein, bacterial reaction center (M.Diesenhofer,
R. Huber, H. Michel) shows alpha helical transmembrane segments |
| 1990 |
High resolution crystal structure
of bacterial porin confirms beta barrel motif for a functional
membrane protein channel |
| 1995 |
Under the guidance of J.C. Venter
The Institute for Genomics Research TIGR publishes the first
full genome sequence of Mycoplasma genitalium, a member
of the archaea branch of life. This landmark publication establishes
Genomics as a new branch of biology changing the way molecular
biologists study the genetics and evolution of organisms. |
| 1999, 2000 |
High resolution structure of Kcsa,
a K+ selective bacterial ion channel solved (R.
MacKinnon); shows the involvement of protein backbone structures
in the selectivity process rather than the expected amino acid
residues. MacKinnon et al.'s work is the start of a very fruitful
period in solving the structures of membrane proteins including
the high resolution structure of a water selective aquaporin
in 2000 (P.
Agre). These channel structures show the mechanisms of high
flux rate and selectivity of small polar and charged molecules
across cell membranes. |
| 2001 |
The first draft of the human
genome is published by competing public and private efforts.
Genome projects of dozens of organisms show that membrane proteins
make up to 30% of the protein set of organisms, from bacteria
to man. |
| |
|
|
|
|
|
