Structural Protein Disorders Flashcards by Garrett Oberst

Quantity of CFTR in membrane is product of

RNA transcribed, efficiency of splicing, fraction correctly folded, and stability of protein in membrane

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PTC and NMR

Premature termination codon

Nonsense mediated decay

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Most common mutation of CF

DeltaF508…leads to improper folding of the protein and is degraded

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Function of CFTR repends on

Activity of ion channel and efficiency of conductance of ions through the channel

Affected by G551D

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Gain of function mutations

Promote abnormal interactions, increase interaction of mutated protein with natural binders, or promote misfolding/aggregation

Cause of most genetic dominance

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Enamelin

Secreted by ameloblasts and ineracts with amelogenin to form molecular scaffolding of highly organized hydroxyapatite crystals

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Amelogenesis Imperfecta (AI)

Mutation in enamelin
Large hypoplastic areas and horizontal rows of pits

Premature stop codon

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AI dominant (x-linked)

P52R mutation in amelogenin or K53X mutation in enamelin

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MMP20

Enamelysin

Processes amelogenin and enamelin as part of normal processing

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MMP20 defects

Recessive cause (loss of function)

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Recessive AI symptoms vs. dominant

Rec - thin and brittle teeth

Dom - grooved, pitter, abnormal

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Gamma-secretase substrates/function

Type 1 transmembrane proteins..includeds APP and Notch

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Presenilin

Makes up active side of gamma secretase

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Mutation in presnilin effect

Soluble Abeta 40 decreases and more aggregation prone Abeta 42 increases

Cleave in down near 3 lysines at boundary of the mmbrane

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How does gain of function come about in presenilin

Normally cleaves near position 50, now changed by single amino acid and produces 42

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Bone composition

Organic - collagen and small amounts of proteoglycans

Inorganic - hydroxyapatite in the form of rod shaped crystals

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Osteoblasts and osteocytes

Blasts - anabolic

Clasts - catabolic

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Surface between osteoclast and bone

Resorption lacuna - provides acidic environment

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Osteocytes

Osteoblasts that become buried in the bone matrix

Cathespin K

Cleaves the triple helix of collagen 1,2 and osteonectin

Cathespin K production

From osteoclasts as procathepsin K which is cleaved by acidic environment

In absence of cathepsin K

Bone formation continues unabated - high mineral content, higher density and fragility

Pyncnodysostosis

Cathespin K mutants (auto recessive)

Pycnodysostosis symptoms

Moderate to short stature
Osteropetrosis - increased bone mineralization and density
Increased bone fragility lead to fractures (especailly clavicle)
Underdevelopment of tips of fingers including nails
Large head with small face, high forehead, dental abnormalities

Hajdu-Cheney Syndrome

Auto dominant in the Notch receptor | Severe bone resorption leading to osteoporosis

Hajdu-Cheney Syndrome symptoms

Poor bone flexibility, short statures, delayed speech and motor, skull malformations and fusions

Mutation of of Hajdu-Cheney

in the Notch receptor, NICD domain,...makes it resistant to degradation, prolonging action in the nucleus

Notch controls

Differentiation of osteoclasts

Notch Hajdu-Cheney mutant shows

Decreased trabeculae, thinner and porous cortical bone

Gamma secretase inhibitor will

Halt osteoclast differentiation

Primary driver of FGF signaling

Interaction with ECM

Embryonic FGF interactions

Antero-posterior patterning Limbs Neural induction and development

Adult FGF interactions

Angiogenesis, keratinocyte, and wound healing

FGF structure

3 extracellular Ig-type domains, a transmembrane domain, and an intracellular tyrosine kinase domain

FGFs bind

Receptors (FGFR1-4) and glycosaminoglycans (GAGs) to form an activated, cell-surface complex

FGFR1 disorders

Pfeiffer, Jackson-Weiss, Antley-Bixler, Osteoglophonic dysplasia, squamous cell lunger cancer, auto-dom Kallmann syndrome, and cleft lip/palate

FGFR2 disorders

Apert, Beare-stevenson, Crouzon, Jackson-weiss, pfeiffer

FGFR3 disorders

Achondroplasia, Crouzon, Hypochondroplasia, and Muenke Syndrome

Muenke Syndrome symptoms

Craniosynostosis (misshapen head/coronal fusions) Facial asymmetry Carpal/tarsal bone fusions...braod thumbs and big toes Mild to moderate sensorineural hearing loss and developmental delay sometimes

Cause of Muenke Syndrome

P250R mutation in extracellular portion FGFR3 leads to gain of function andallowing bones to fuse sooner than normal

Muenke syndrome inheritance

Auto-dom - chromosome 4

2 symptoms with facial asymmetries

Crouzon and Muenke

Achondroplasia mutation

Auto dominant, sporadic in 80% of cases | FGFR3 (G360R mutation)...leave FGF-FGFR3 on as a gain of function mutation and leaves short limb bones

Achondroplasia symptoms

Large skull, prom forehead, short limbs, long trunk, spinal cord compression

Normal FGF-FGFR3 function

Negative regulator of bone growth and inhibits production of cartilage by chondrocytes

FGFR3 knock-out mice show

Long bones, elongated vertebrae, and long tails

CNP mechanism

Binds to NPRB of the chondrocytes...creates competing signal that inhibits MAPK cascade that FGFR3 uses to slow bone growth...basically CNP has antagonistic role in bone growth compared to FGF