a Domain structures

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a- Domain structures Regions inside membranes
very frequently a-helices whose surfaces are
covered by hydrophobic side chains. Fibrous
proteins, ex. Keratin, in skin, hair, feathers or
muscle proteins like myosin and dystrophin are
a-helical for the most part. Dont want
hydrophobic side chains pointing out!
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Coiled-coil a- helices contain a repetitive
heptad amino acid sequence pattern Basis for
some fibrous proteins and can extend over many
hundreds of amino acid residues. 2 right handed
helices twist to form a left handed super-coil
and has 3.5 residues (NOT 3.6) per turnstrong
stable arrangement The pattern of side chains
interactions repeats every seven residues (2
turns) heptad repeat
Diagram of heptad repeat in a coiled-coil
structure showing the backbone of the polypeptide
chain. Very hydrophobic.
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The heptad repeat is often a leucine
(hydrophobic) or isoleucine. The side chains of
these residues pack together in a coiled-coil
every second turn at position a we usually have
another hydrophobic residue to help pack.
Residues e and g which border the hydrophobic
core are often charged. These side chains often
form salt bridges between the helices that define
the relative chain alignment and orientation.
Look at the 1o sequence to determine what type
of motif will occur.
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The 4-helix bundle is a common domain structure
in a-proteins 2 a-helices packed together into a
coiled-coil are building blocks within a domain
or fiber but are not sufficient to form a
complete domain. The simplest and most common
a-helical domain consists of 3 a-helices arranged
in a bundle with the helical axes almost parallel
to each other 4-helix bundle Most common
domain 2 sets of coiled- coils that twist
together to create a hydrophobic core
Hydrophobic core
Hydrophilic
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a- helical domains are sometimes large and
complex. The structures of several enzymes are
known in which long polypeptide chains of 300-400
amino acids are arranged in more than 20
a-helices packed together in a complex pattern to
form a globular domain.
2 pairs parallel helices
Anti-parallel helices
The polypeptide chain of this monomeric enzyme
has 618 amino acids, of which the N-terminal 450
residues form one-helical domain. This domain is
built up from 27 a helices arranged in a
2-layered ring with a rt. Handed super-coil twist.
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a/ß structures Most popular domain
structurescentral parallel or mixed ß-sheet
surrounded by a-helices. All the glycolytic
enzymes are a/ßs, so are proteins that bind and
transport metabolites. In a/ß proteins, binding
crevices are formed by loop regions. These
regions DONT contribute to stability of the
fold, but DO participate in binding and catalytic
action.
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3 Main classes of a/ß structures
Core of twisted parallel ß-strands like staves in
a barrel. a-helices connect these. Often called
TIM barrels (triosephosphate isomerase) where it
was first observed
Open twisted ß-sheet surrounded by helices.
Often called the Rossman fold (in lactate
dehydrogenase) All parallel ß-strands
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Horseshoe fold/ Leucine rich motifs
Diagram of ribonuclease inhibitor. Built of
repetitive ß-loopa-motifs to resemble a
horseshoe with a 17-stranded parallel ß- sheet on
the inside and 16 a- helices on the outside.
The role of the conserved leucines is to help
stabilize the ß-loop a-motifs.
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In barrels the hydrophobic side chains of the
a-helices are packed against hydrophobic side
chains of the ß-sheet. The helices are
anti-parallel and adjacent to the ß-strands they
connect. Thus, the barrel is provided with a
shell of hydrophobics. Since the side chains of
consecutive amino acids of a ß-strand are on
opposite sides of the ß-sheet every 2nd residue
of the strand contributes to the hydrophobic
shell, the other side chain points in and forms a
hydrophobic core. The 8 stranded a-ß barrel is
one of the largest and most regular of all domain
structures. It needs a minimum of 200 residues
to form.
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The active site is formed by loops at one end of
the a/ß barrel Generally situated in the bottom
of a funnel-shaped pocket created by the 8 loops
that connect the carboxy end of the ß-strands
with the amino end of the a-helices. Residues
that participate in binding and catalysis are in
these loop regions.
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Leucine rich motifs form an a/ß horseshoe
fold Leu rich motifstandem homologous amino
acid sequences of about 20-30 residueshave been
identified in a variety of proteins. 2
motifs _at_ 28 and 29 residue segment Each repeat
forms a right handed ß-loop-a like weve seen
before. Sequential ß-loop-as are joined
together like is the a-ß barrel structures. The
ß-strands form a parallel ß-sheet and all the
a-helices are on one side of the ß-sheet.
However, instead of forming a closed barrel they
form a curved open structure that looks like a
horseshoe.
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One side of the ß-sheet faces the a-helices and
participates in a hydrophobic core between
a-helices and the ß-sheet the other side of the
sheet is exposed to solventthe a/ß structures
DONT have this. The leucine residues in this
leucine rich motif form a hydrophobic core
between the ß-sheet and the a-helices.
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Leucine residues _at_ positions 2,5 and 7 from the
ß-strand of the motif pack against leu 20 and 24
of the a-helix to form the main part of the
hydrophobic region. Leu residue 2, 5, 7, 12, 20
and 24 are invariant in type A and B repeats with
the ribonuclease inhibitor. 68 other proteins
show that 20 and 24 can be other hydrophobics.
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• Conclusions
• a/ß structures are the most frequent and most
  regular of the protein structures
• 3 classes
• Central core of approx. 8 parallel ß-strands
  arranged like staves of a barrel, surrounded by
  a-helices.
• Open-twisted or mixed ß-sheet with a-helices on
  both sides.
• Leucine rich motifs in which a large number of
  parallel ß-strands form a curved ß-sheet with all
  the a-helices on the outside.