Protein structures in the PDB

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Protein structures in the PDB
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Domains

• proteins can be modular
• single chain may be divisible into smaller
  independent units of tertiary structure called
  domains
• domains are the basic unit of structure
  classification
• different domains in a protein are also often
  associated with different functions carried out
  by the protein.

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Definition of domain

• A polypeptide or part of a polypeptide chain
  that can independently fold into a stable
  tertiary structure...
• from Introduction to Protein Structure, by
  Branden Tooze
• Compact units within the folding pattern of a
  single chain that look as if they should have
  independent stability.
• from Introduction to Protein Architecture, by
  Lesk

MBP Figure to go here
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Motif (Supersecondary Structure)

• there are certain favored arrangements of
  multiple secondary structure elements that recur
  again and again in proteins--these are known as
  motifs or supersecondary structures
• a motif is usually smaller than a domain but can
  encompass an entire domain

greek key
beta-alpha-beta
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Protein Taxonomy-The CATH Hierarchy

• 1. Divide PDB structure entries into domains
  (using domain recognition algorithms--the domain
  is the fundamental unit of structure
  classification
• 2. Classify each domain according to a five
  level hierarchy

Class Architecture Topology Homologous
Superfamily Sequence Family
the top 3 levels of the hierarchy are purely
phenetic--based on characteristics of the
structure, not on evolutionary relationships
the bottom two levels include some phyletic
classification as well-- groupings according to
putative common ancestry based on structural
similarity, functional similarity, and sequence
similarity
protein evolution is not well understood-- there
is to date no purely phyletic classification
system
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Class

• In the CATH hierarchy, Class simply describes
  what type of secondary structure is present.
• There are only four classes
• mainly a
• mainly b
• a b
• few secondary structures
• 90 of structures are trivial to assign at this
  level.

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Architecture

• Architecture is hard to define precisely
• In CATH it is defined broadly as describing
  general features of protein shape such as
  arrangements of secondary structure in 3D space
• It does not define connectivities between
  secondary structural elements--thats what the
  topology level does. It does not even explicitly
  define directionality of secondary structure,
  e.g. parallel or antiparallel beta-sheets.
• in CATH, architectures are presently assigned
  manually, by visual inspection.
• lets look at some architectures!

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Some mostly beta architectures
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Some mixed alpha-beta architectures
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Topology (Fold)

• if two proteins have the same topology, it means
  they have the same number and arrangement of
  secondary structures, and the connectivities
  between these elements are the same.
• this is also sometimes called the fold of a
  protein.
• in CATH, automated structure alignment is used
  to group proteins according to topology. We will
  discuss this later.
• we will now look at some examples which
  illustrate differences in topology.

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Topology differences in connectivity

• example a four-stranded antiparallel beta-sheet
  can have many different topologies based on the
  order in which
• the four beta-strands are connected.

greek key
up-and-down
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Topology differences in handedness

• example in a beta-alpha-beta motif, if the two
  parallel strands are oriented to face toward you,
  the helix can be either above or below the plane
  of the strands.

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Visualizing protein topology--TOPS cartoons

• up trianglesup-facing beta strands
• down trianglesdown-facing beta strands
• horizontal rows of trianglesbeta sheets (beta
  barrel would be a ring of triangles)
• circleshelices

• linesloops
• if loops enter from top, line drawn to ctr.
• if loops enter from bottom, line drawn to
  boundary

fold above is clearly an antiparallel
beta-sandwich
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Visual summary of top three levels of CATH
hierarchy
CLASS
ARCHITECTURE
TOPOLOGY
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Discovery of New Folds

• structural taxonomy reveals that although
  structures are being solved more rapidly than
  ever, fewer and fewer of them have new folds!
  Will we get them all soon?

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Homologous superfamily/Sequence family

• The lowest two levels in the CATH hierarchy
  relate to common ancestry
• some, but not all proteins with the same fold
  show evidence of common ancestry
• the surest way of identifying common ancestry is
  that two proteins have sequences roughly gt30
  identical (sequence family level)
• if protein sequences are not that similar, common
  ancestry may still be inferred on the basis of a
  combination of structural and functional
  similarity, and possibly weak sequence similarity
  (homologous superfamily level)

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Multifunctional Superfolds
some architectures have many folds-- superarchite
cture
some folds have many homologous superfamilies, whi
ch means they are used for a variety of
functions. these are called superfolds
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Common core

• structures need not share exactly the same
  number, type and connectivity of secondary
  structural elements to be grouped into a single
  fold type.
• in fact, evolutionarily related proteins often
  share a common core of structurally related
  elements but may differ in presence or absence of
  a secondary structure element or two.

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Problems in Fold Classification

• Structure space has a continuous aspect,
  especially in certain types of folds, which makes
  clustering structures into fold families
  difficult. This is an inherent problem for any
  classification method based on hierarchical
  clustering.
• It seems reasonable to group as having the same
  fold proteins which share some common core but
  differ in addition/subtraction of a few secondary
  structure elements.
• But this can lead to unnaturally large and
  diverse fold families via the Russian doll effect
  and motif overlap.

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Russian Doll Effect

• A continuous range of slight size differences
  will lead to clustering proteins of very
  different size. small--gt medium--gtlarge.

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Motif Overlap

• Motif overlap effects Sometimes two proteins
  will share a common core but one of them will
  share a slightly different (but not necessarily
  larger) common core with a third protein. A
  continuous range of overlapping common cores
• AB--gtBC--gtCD will lead to grouping
  proteins that have no common core.

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Comparison of SCOP and CATH Hierarchies

• SCOP CATH
• class class
• architecture
• fold topology
• homologous superfamily
• superfamily
• family sequence family
• domain domain

CATH more directed toward structural
classification, SCOP pays more attention to
evolutionary relationships
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Another SCOP/CATH difference

• in CATH, there is one class to represent mixed
  alpha-beta
• in SCOP there are two
• a/b beta structure is largely parallel,
  made of bab motifs
• ab alpha and beta structure segregated to
  different parts of structure

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SCOP and CATH

• they have in common that they are hierarchical
  and based on abstractions
• they both include some manual aspects and are
  curated by experts in the field of protein
  structure
• are there automated methods for structure
  classification/comparison?