Cockayne syndrome

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Cockayne syndrome

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Cockayne Syndrome

Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder caused by a defect in transcription-coupled nucleotide excision repair (TC-NER). It was first described by E.A. Cockayne in 1936, characterised by cachectic dwarfism, deafness, and pigmentary retinal degeneration.

Genetics and Molecular Basis

CS results from mutations in two main genes:

Gene	Alias	Frequency
CSB	ERCC6	~2/3 of cases
CSA	ERCC8	~1/3 of cases

Both genes are part of the nucleotide excision repair (NER) pathway. Their specific role is in transcription-coupled repair - recognising and repairing DNA lesions (particularly UV-induced pyrimidine dimers) that stall RNA polymerase during active transcription. When RNA polymerase stalls at a DNA lesion, CSB and CSA recruit the repair machinery and chromatin remodellers to clear the blockage. Without functional TC-NER, transcription is persistently blocked at DNA damage sites, leading to cell death and progressive tissue degeneration.

Additional CS-associated mutations occur in XPB, XPD, and XPG - these produce the XP-Cockayne overlap syndrome, which carries elevated skin cancer risk unlike classical CS.

The inheritance is autosomal recessive with a 1-in-4 recurrence risk for siblings.

Fitzpatrick's Dermatology, p. 2384-2385
Andrews' Diseases of the Skin, p. 668

Clinical Subtypes

Type	Onset	Severity
CS Type I (classic)	2nd year of life	Moderate, slowly progressive
CS Type II (severe)	Infancy/congenital	Severe, rapid deterioration
CS Type III (mild)	Late onset	Mild, longer survival
COFS syndrome	Congenital	Most severe (microcephaly, cataracts, arthrogryposis)
UVSS	-	Mildest - UV sensitivity only, no systemic features

Clinical Features

Cutaneous

Photosensitivity: acute, painful burning on minimal sun exposure (in ~75% of patients) - without the freckling or pigmentary abnormalities of xeroderma pigmentosum
Photodermatitis with telangiectasia, atrophy, and scarring
No increase in skin cancer (distinguishes CS from XP)
Loss of subcutaneous fat giving a "wizened," cachectic appearance
Nail dystrophy, hair abnormalities, cyanotic acral oedema of hands and feet
Large, cyanotic-appearing hands and feet

Neurological

Developmental delay and progressive intellectual deterioration
Microcephaly, progressive growth failure
Peripheral neuropathy (primary segmental demyelination), reduced nerve conduction velocities
Spastic weakness and ataxia; occasionally athetosis
Sensorineural hearing loss (nerve deafness), progressive
Normal pressure hydrocephalus
Tigroid leukodystrophy (segmental myelin loss)
Basal ganglia calcification (putamen)
Cerebellar cortical atrophy on pathology
CSF is normal; no diagnostic biochemical findings

Ocular

Progressive pigmentary retinal degeneration ("salt-and-pepper" retina), leading to blindness
Cataracts (early-onset)
Microphthalmia; sunken eyes (enophthalmia) due to loss of orbital fat
Photophobia, diminished tearing, conjunctivitis, corneal scarring
Iris atrophy, poorly reactive pupils
Pendular nystagmus
Abnormal electroretinogram

Somatic / Other

Stunted growth - evident by 2nd-3rd year
Prognathism, beaked/prominent nose, sunken eyes - facies resembling progeria or "bird-headed dwarfism"
Anhidrosis, poor lacrimation
Dental: tooth enamel hypoplasia
Kyphoscoliosis, flexion contractures
Cryptorchidism
Shortened lifespan
Adams and Victor's Principles of Neurology, p. 982
Fitzpatrick's Dermatology, p. 2384-2385

Pathology

Small brain
Striatal and cerebellar calcifications
Leukodystrophy resembling Pelizaeus-Merzbacher disease
Severe cerebellar cortical atrophy
Peripheral nerves: primary segmental demyelination

Diagnosis

Mandatory major criteria (all three required):

Developmental delay
Progressive growth failure
Progressive microcephaly

Minor criteria (3 out of 5 required):

Cutaneous photosensitivity
Pigmentary retinopathy and/or cataracts
Progressive sensorineural hearing loss
Tooth enamel hypoplasia
Enophthalmia (sunken eyes)

Brain imaging criteria (supportive):

White matter hypomyelination
Cerebellar atrophy or hypoplasia
Bilateral calcifications of the putamen

Laboratory testing:

Cellular UV hypersensitivity assay - CS cells show impaired recovery of RNA synthesis after UV irradiation (while XP cells show reduced unscheduled DNA synthesis - a useful distinguishing test)
Molecular: sequencing of CSA (ERCC8) and CSB (ERCC6) genes
Prenatal diagnosis by linkage analysis in families with a known mutation

Comparison: CS vs. Xeroderma Pigmentosum (XP)

Feature	Cockayne Syndrome	Xeroderma Pigmentosum
DNA repair defect	TC-NER (transcription-coupled)	GG-NER (global genome)
Skin cancer	No increase	Markedly elevated
Freckling/pigmentation	Absent	Prominent
Dwarfism	Present	Absent
Neurodegeneration	Present	Present (in some)
Hearing loss	Present	Absent (usually)
Deafness	Yes	No

XP-Cockayne Overlap Syndrome

Patients with mutations in XPB, XPD, or XPG can display features of both XP and CS - they have the skin cancer risk of XP plus the neurological degeneration of CS. This reflects the dual role of TFIIH complex subunits in both transcription and DNA repair.

Management

There is no curative treatment for CS. Management is supportive:

Sun protection (clothing, sunscreen, avoidance of UV)
Ophthalmologic care (cataract surgery, lubricating eye drops for poor lacrimation)
Hearing aids for sensorineural hearing loss
Physiotherapy and orthopaedic care for spasticity and contractures
Nutritional support / gastrostomy for feeding difficulties
Monitoring and treatment of complications (cataracts, hydrocephalus)
Note: Valproate is contraindicated in Cockayne syndrome - fatal liver failure has been reported (Harriet Lane Handbook, p. 7302)
Genetic counselling for families

Key Mnemonics / Summary Points

CS = Cachectic dwarfism + Sensory deficits (deaf, blind) + Sun sensitivity (no cancer)
Gene: CSB (ERCC6) > CSA (ERCC8) - both = transcription-Coupled repair
NO skin cancer (TC-NER defect doesn't leave unrepaired lesions in non-transcribed regions for carcinogenesis the same way GG-NER deficiency does)
XP-CS overlap: mutations in XPB/XPD/XPG - SKIN CANCER RISK returns

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Transcription

Transcription is the process by which genetic information encoded in DNA is copied into RNA. It is the first step of gene expression, following the central dogma: DNA → RNA → Protein.

1. Key Terminology: Strands of DNA

Strand	Also Called	Direction	Role
Template strand	Antisense strand	3' → 5'	Read by RNA polymerase
Coding strand	Sense/non-template strand	5' → 3'	Identical in sequence to the RNA transcript (with T→U)

By convention, gene sequences are written as the coding strand, 5' to 3'. The start point of transcription is designated +1; sequences upstream (before it) are negative (-1, -2, etc.).

Basic Medical Biochemistry, p. 442-444

2. RNA Polymerases

Prokaryotes

A single RNA polymerase (a multi-subunit holoenzyme) handles all transcription. It contains a core enzyme plus a sigma (σ) factor, which confers promoter recognition specificity. The most common is σ70 in E. coli.

Eukaryotes (3 nuclear polymerases)

Polymerase	Products
RNA Pol I	rRNA (28S, 18S, 5.8S) - initially as a 45S primary transcript
RNA Pol II	mRNA + microRNA (miRNA)
RNA Pol III	tRNA + 5S rRNA + other small RNAs

The mitochondria has its own separate RNA polymerase for the mitochondrial genome.

RNA polymerases, unlike DNA polymerases, do not require a primer to start synthesis.
They also lack extensive error-checking (proofreading) capability.
Synthesis always proceeds 5' to 3', reading the template 3' to 5'.
Basic Medical Biochemistry, p. 442; Tietz Textbook of Laboratory Medicine, p. 1527

3. Promoters

The promoter is a DNA sequence upstream of the transcription start site that specifies where RNA polymerase binds to initiate transcription.

Prokaryotic Promoters (E. coli)

-10 box (Pribnow box): consensus sequence TATAAT, recognized by sigma factor σ70
-35 region: consensus sequence TTGACA

Eukaryotic Promoters (RNA Pol II)

TATA box (Hogness box): consensus TATA(A/T)A, located ~-25 to -40 from the start site. Found in only ~12.5% of promoters - these are highly regulated genes. Housekeeping genes often lack a TATA box.
BRE (TFIIB-recognition element): GC-rich sequence, upstream of TATA
Initiator element (Inr): most common core promoter element (~50% of promoters), at the +1 site
DPE (downstream promoter element) and MTE (motif ten element): located downstream of +1
Promoter-proximal elements: in the -100 to -200 region, bind regulatory proteins
Enhancers: distal elements that can be thousands of base pairs upstream or downstream; they stabilize RNA Pol binding but do not define the initiation site. The DNA folds back on itself to allow enhancer-bound transcription factors to interact with the RNA Pol complex.
Basic Medical Biochemistry, p. 444

4. Stages of Transcription

Initiation

Transcription factors bind to the promoter
For RNA Pol II: TFIID binds the TATA box first, then recruits TFIIA, TFIIB, TFIIE, TFIIF, TFIIH, and RNA Pol II to form the pre-initiation complex (PIC)
TFIIH (which contains XPB and XPD helicases - relevant to Cockayne syndrome and XP) unwinds the DNA around the start site
The double-stranded DNA separates; RNA synthesis begins

Elongation

RNA Pol moves along the template strand 3'→5', synthesizing RNA 5'→3'
Nucleotides are added to the free 3'-OH of the growing chain
The DNA strands separate ahead of the polymerase and rejoin behind it (the "transcription bubble")
No primer is needed

Termination

Prokaryotes: a termination factor (Rho) recognizes a DNA termination sequence, OR intrinsic termination occurs via hairpin loop formation in the RNA
Eukaryotes (RNA Pol II): termination is coupled to polyadenylation - transcription continues past the coding region until poly(A) signals are encountered, then RNA is cleaved and the polymerase released
Tietz Textbook of Laboratory Medicine, p. 1527-1528

5. Post-Transcriptional Processing (Eukaryotes)

The primary transcript (heterogeneous nuclear RNA = hnRNA or pre-mRNA) undergoes three major modifications in the nucleus before it becomes mature mRNA:

Eukaryotic mRNA synthesis - hnRNA processing including 5'-cap, poly(A) tail, and splicing to remove introns

A. 5' Capping

After ~20-30 nucleotides have been transcribed, a 7-methylguanosine (m7G) cap is added to the 5' end via an unusual 5'→5' triphosphate linkage
A methyltransferase methylates the N7 position of the G residue
Three cap types exist: Cap 0, Cap 1, Cap 2 (based on ribose methylation of the first and second nucleotides)
Functions: protects mRNA from degradation by 5' exonucleases, facilitates nuclear export, and promotes ribosome attachment for translation

B. 3' Polyadenylation

The signal sequence AAUAAA (or a variant) is encoded in the 3' UTR of the pre-mRNA
The pre-mRNA is cleaved at a specific point ~10-30 nt downstream of AAUAAA
Poly(A) polymerase adds ~200 adenylate residues to the 3' end
Functions: stability of mRNA, nuclear export, and enhancement of translation
Note: histone mRNAs are a notable exception - they are not polyadenylated

C. RNA Splicing

Introns are non-coding sequences interspersed between coding exons
Splicing signals:
- 5' splice site (donor): GT dinucleotide (GU in RNA)
- 3' splice site (acceptor): AG dinucleotide
- Branch site: an intronic sequence ~20-50 nt upstream of the 3' splice site (contains an adenosine residue)
The spliceosome (a complex of 5 small nuclear RNAs - U1, U2, U4, U5, U6 - and associated proteins called snRNPs / "snurps") catalyzes splicing
Mechanism: two transesterification reactions form a lariat intermediate (the intron loops back on the branch site A), then exons are joined and the intron lariat is released and degraded
Alternative splicing allows a single gene to generate multiple different protein isoforms

Clinical relevance: Autoantibodies against snRNPs (Smith antigens) are a hallmark of Systemic Lupus Erythematosus (SLE) - snRNPs were actually discovered using antibodies from SLE patients.

Emery's Medical Genetics, p. 25-26; Basic Medical Biochemistry, p. 449

6. Other RNA Products

rRNA (RNA Pol I)

rRNA genes are clustered in the nucleolus
A single 45S primary transcript is cleaved into 28S, 18S, and 5.8S rRNA
These combine with ribosomal proteins to form the large (60S) and small (40S) ribosomal subunits

tRNA (RNA Pol III)

Transcribed as precursor tRNAs, then processed by cleavage and base modification
Cloverleaf secondary structure with 4 loops:
- D-loop (contains dihydrouridine)
- Anticodon loop (contains the 3-base anticodon)
- TΨC-loop (contains ribothymidine T and pseudouridine Ψ)
- Variable loop
The 3'-end has the invariant CCA sequence where the amino acid attaches
RNA Pol III recognizes a split internal promoter within the tRNA gene itself (+8 to +19 and ~30-60 bp downstream)

7. Prokaryote vs. Eukaryote Transcription: Key Differences

Feature	Prokaryotes	Eukaryotes
RNA polymerases	1	3 (nuclear) + mitochondrial
Location	Cytoplasm	Nucleus
Coupled transcription-translation	Yes	No (nuclear membrane separates the processes)
Pre-mRNA processing	Minimal	Extensive (capping, splicing, polyadenylation)
Introns	Rare	Present in most genes
One mRNA = one protein?	No (polycistronic)	Yes (monocistronic)
Promoter	-10 and -35 boxes	TATA box, Inr, BRE, DPE, MTE

8. Regulation of Transcription

Transcription is the primary level at which gene expression is regulated:

Transcription factors: proteins that bind specific DNA sequences (via helix-turn-helix, zinc finger, leucine zipper domains) and either activate or repress RNA Pol binding
Activators: bind enhancers or promoter-proximal elements; stabilize RNA Pol at the promoter; increase transcription rate
Repressors: bind the promoter or operator region and block RNA Pol binding, reducing or silencing transcription
Transcription factors generally bind as dimers and have at least 3 functional domains: DNA-binding, dimerization, and transcriptional activation/repression
Additional regulation by epigenetic mechanisms (DNA methylation, histone acetylation/methylation) that control chromatin accessibility

9. Clinically Relevant Inhibitors

Drug/Toxin	Mechanism	Relevance
Rifampin	Inhibits bacterial RNA polymerase (binds β subunit)	Treatment of tuberculosis
α-Amanitin (death cap mushroom)	Inhibits eukaryotic RNA Pol II (and at high doses, Pol III)	Mushroom poisoning; no antidote
Actinomycin D	Intercalates DNA, blocks elongation by all RNA polymerases	Used in cancer research/chemotherapy

Basic Medical Biochemistry, p. 465

Summary Flow

DNA (double-stranded)
     ↓  [RNA Polymerase + Transcription Factors bind promoter]
Primary RNA Transcript (pre-mRNA / hnRNA)
     ↓  [5' Capping]
     ↓  [3' Polyadenylation]
     ↓  [Splicing — spliceosome removes introns]
Mature mRNA
     ↓  [Nuclear export through nuclear pores]
Cytoplasm → Ribosomes → TRANSLATION → Protein

Post translational modifications

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Post-Translational Modifications (PTMs)

Post-translational modification (PTM) is any covalent chemical change to a protein that occurs after translation is complete. PTMs adjust a protein's physical and chemical properties, conformation, stability, activity, subcellular localization, and interactions - massively expanding the functional diversity of the proteome far beyond what the ~20,000 human genes alone could encode.

The most common naturally occurring PTMs are: acetylation, phosphorylation, ubiquitination, glycosylation, methylation, and proteolytic cleavage.

Rheumatology (Elsevier 2022), p. 2240
Emery's Elements of Medical Genetics, p. 26

1. Phosphorylation

What: Addition of a phosphate group (–PO₄²⁻) to the hydroxyl group of serine, threonine, or tyrosine residues.

Enzymes: Protein kinases add phosphate (using ATP); protein phosphatases remove it - making phosphorylation rapidly reversible.

Effects:

Activates or inactivates enzymes
Creates docking sites for other signaling proteins (e.g., SH2 domains recognize phosphotyrosine)
Drives conformational changes

Key roles:

Central mechanism of intracellular signal transduction (e.g., receptor tyrosine kinases, MAPK cascade, JAK-STAT)
Regulation of cell cycle (cyclin-dependent kinases)
Metabolic regulation (glycogen phosphorylase, pyruvate dehydrogenase)

Clinical relevance: Dysregulated kinases drive cancer (e.g., BCR-ABL in CML → imatinib target). Phosphatases like SHP-1 shut down immune signaling - their loss causes autoimmunity.

2. Glycosylation

Addition of sugar (carbohydrate) chains to proteins. Two main types:

N-linked glycosylation

Sugars are attached to the amide nitrogen of asparagine (Asn) in the sequon Asn-X-Ser/Thr (X ≠ Pro)
Begins in the rough ER: a 14-sugar oligosaccharide (GlcNAc + mannose + glucose) pre-assembled on dolichol phosphate is transferred en bloc to the Asn
Further processed/trimmed in ER and Golgi - glucose and some mannose residues are removed, then other sugars (GlcNAc, galactose, fucose, NANA/sialic acid) are added
Tunicamycin blocks N-linked glycosylation
Congenital Disorders of Glycosylation (CDG): rare syndromes from defects in N-linked glycosylation
Mannose-6-phosphate (M6P) targeting: in the Golgi, N-linked glycoproteins destined for lysosomes are phosphorylated at mannose residues; M6P receptors recognize this tag and direct vesicles to lysosomes
- I-Cell Disease: GlcNAc phosphotransferase deficiency → no M6P tag → lysosomal enzymes secreted extracellularly instead of reaching lysosomes

O-linked glycosylation

Sugars attached to the hydroxyl of serine or threonine
Assembled one sugar at a time in the Golgi (not en bloc)
GalNAc is the first sugar added (O-GalNAc glycans, "mucin-type")
Less complex consensus sequence requirement

Functions of glycosylation: protein stability, protection from proteolysis, cell-cell recognition, immune function (ABO blood groups), antigenicity, receptor binding.

Medical Physiology, p. 899-903
Biochemistry (Lippincott 8e), p. 482-484

3. Ubiquitination

What: Covalent attachment of the small protein ubiquitin (8.5 kDa, 76 amino acids) to lysine residues of target proteins.

Enzymatic cascade (three steps, requires ATP):

Enzyme	Name	Function
E1	Ubiquitin-activating enzyme	Activates ubiquitin in ATP-dependent reaction
E2	Ubiquitin-conjugating enzyme	Transfers ubiquitin from E1 to E3
E3	Ubiquitin ligase	Selects the substrate; transfers ubiquitin to target protein's Lys

A polyubiquitin chain (≥4 ubiquitins) is required to target a protein for proteasomal degradation.

Two key linkage types - linked through different lysines of ubiquitin itself:

Linkage	Effect
K48-linked polyubiquitin	Targets protein to 26S proteasome for degradation
K63-linked polyubiquitin	Acts as signaling scaffold (e.g., NF-κB activation via TRAF6) - NOT degradation

Single ubiquitin or di-ubiquitin on membrane receptors targets them to lysosomes for degradation.

The 26S Proteasome

Proteasome-mediated degradation showing E1/E2/E3 cascade, polyubiquitin chain formation, 26S proteasome complex (19S RP + 20S CP), and ubiquitin recycling by DUBs

20S core particle (CP): barrel-shaped, contains proteolytic active sites - cleaves polyubiquitinated protein into short peptides and amino acids
19S regulatory particles (RP): caps on both ends - the "lid" recognizes polyubiquitin tags and unfolds the protein; the "base" releases degradation products
DUBs (deubiquitinating enzymes): remove and recycle ubiquitin

Targets of ubiquitin-proteasome degradation:

Misfolded or denatured proteins
Short-lived regulatory proteins: mitotic cyclins, transcription factors, tumor suppressors/promoters
Proteins tagged by E3 ligases after phosphorylation (e.g., Cbl ligase targets phosphotyrosine proteins)

Clinical relevance:

Proteasome inhibitors (e.g., bortezomib) are used to treat multiple myeloma
Parkinson's disease: α-synuclein aggregates partly due to impaired ubiquitin-proteasome function
Cancer: many oncoproteins escape ubiquitin-mediated degradation
Histology (Gartner), p. 169-170
Janeway's Immunobiology 10e, p. 286-287

4. Acetylation

What: Addition of an acetyl group (–COCH₃) from acetyl-CoA to the ε-amino group of lysine (or the α-amino terminus).

Histone acetylation (most studied):

Catalyzed by HATs (histone acetyltransferases) - opens chromatin for transcription
Reversed by HDACs (histone deacetylases) - closes chromatin, represses transcription
Mechanism: acetylation neutralizes the positive charge of lysine, reducing its attraction to the negatively charged DNA backbone → chromatin relaxes → transcription factors gain access

Non-histone proteins: acetylation can regulate protein stability (e.g., acetylation of p53 activates it), protein-protein interactions, and enzyme activity.

Clinical relevance:

HDAC inhibitors (e.g., vorinostat) are used as cancer therapies
HAT/HDAC imbalance contributes to cancer, inflammatory diseases (rheumatoid arthritis, asthma), and neurodegeneration
Rheumatology, p. 3692-3714

5. Methylation

What: Addition of a methyl group (–CH₃) to lysine or arginine residues by methyltransferases, using S-adenosylmethionine (SAM) as the methyl donor. Removed by demethylases.

Unlike acetylation, methylation does NOT change the charge of lysine - its effects depend entirely on which residue is methylated and by how many methyl groups.

Histone methylation and gene regulation (context-dependent):

Modification	Association
H3K4me, H3K36me, H3K79me	Active transcription
H3K9me, H3K27me	Repressed transcription / heterochromatin

This differential pattern constitutes part of the "histone code" - the idea that combinations of histone modifications specify transcriptional outcomes.

DNA methylation (related but distinct PTM of the DNA itself):

Methylation of cytosine at CpG dinucleotides → recruits methyl-CpG-binding proteins (MeCP2, MBD1-3) → tethers HDAC complexes → chromatin silencing
Critical for genomic imprinting (e.g., Prader-Willi, Angelman, Beckwith-Wiedemann syndromes)
Medical Physiology, p. 147
Harrison's Internal Medicine 22e

6. Proteolytic Cleavage

What: Irreversible removal of part of the polypeptide chain by protease cleavage.

Types and examples:

Type	Example
Signal peptide removal	Cleavage of N-terminal signal sequence in ER lumen immediately after translocation
Zymogen activation	Trypsinogen → trypsin; pepsinogen → pepsin; prothrombin → thrombin
Prohormone processing	Proinsulin → insulin + C-peptide; pro-opiomelanocortin → ACTH, β-endorphin, MSH
Viral polyprotein cleavage	HIV-1 protease cleaves the gag-pol polyprotein (target of protease inhibitors)
Caspase activation	Apoptotic cascade - procaspases cleaved to active caspases

Emery's Medical Genetics, p. 26

7. Disulfide Bond Formation

What: Covalent oxidation between two cysteine thiol (–SH) groups to form –S–S–.

Where: Only in oxidizing compartments - the ER lumen and extracellular space. The cytosol is a reducing environment and does not support disulfide bonds.

Enzyme: Protein disulfide isomerase (PDI) in the ER lumen - catalyzes both formation and rearrangement of disulfide bonds until the thermodynamically most stable conformation is reached.

Importance: Stabilizes tertiary and quaternary protein structure (e.g., immunoglobulins, collagen, insulin - the A and B chains of insulin are held together by disulfide bonds).

8. Hydroxylation

What: Addition of –OH to proline → hydroxyproline, and lysine → hydroxylysine.

Key example - Collagen synthesis:

Prolyl and lysyl hydroxylases act on collagen chains in the ER
Requires Vitamin C (ascorbate) as an essential cofactor
Hydroxyproline stabilizes the collagen triple helix through hydrogen bonding
Hydroxylysine provides sites for glycosylation and for crosslinking between collagen fibrils

Scurvy: Vitamin C deficiency → failure of proline hydroxylation → unstable collagen → bleeding gums, poor wound healing, perifollicular hemorrhages.

Basic Medical Biochemistry, p. 1887

9. Lipid Modifications (Membrane Targeting)

These modifications anchor proteins to cell membranes:

Modification	Lipid	Location	Example
Myristoylation	Myristic acid (C14)	N-terminus (Gly)	Src kinase
Palmitoylation	Palmitic acid (C16)	Cys residues	Ras, G proteins
Prenylation (farnesylation, geranylgeranylation)	Isoprenoid	C-terminus (CAAX motif)	Ras, Rho GTPases
GPI anchor	Glycosylphosphatidylinositol	C-terminus	CD55, CD59, prion protein

GPI-linked proteins: synthesized as transmembrane proteins in the ER, then their lumen-facing domain is cleaved and transferred to the GPI lipid anchor. They remain in the outer leaflet of the plasma membrane.

Paroxysmal nocturnal hemoglobinuria (PNH): defect in GPI anchor synthesis (PIG-A gene mutation) → loss of CD55 and CD59 from RBC surfaces → uncontrolled complement activation → hemolysis.

Medical Physiology, p. 907

10. Other Important PTMs

PTM	Target residue	Key function
SUMOylation	Lys	Protein-protein interactions, nuclear transport, transcription regulation
Nitrosylation	Cys (S-nitrosylation)	Signaling by nitric oxide
Carboxylation	Glu → γ-carboxyglutamate	Clotting factors II, VII, IX, X require Vitamin K; bind Ca²⁺
ADP-ribosylation	Arg, Glu	Bacterial toxins (cholera, diphtheria); DNA repair (PARP)
Formylation	Various	Detected by MS; changes protein weight

Summary Table of Major PTMs

PTM	Residue Targeted	Reversible?	Primary Functions
Phosphorylation	Ser, Thr, Tyr	Yes (phosphatases)	Signaling, enzyme regulation
N-linked glycosylation	Asn	Partially	Folding, stability, trafficking, immunity
O-linked glycosylation	Ser, Thr	Yes	Mucin structure, signaling
Ubiquitination (K48)	Lys	Yes (DUBs)	Proteasomal degradation
Ubiquitination (K63)	Lys	Yes (DUBs)	Signaling scaffold
Acetylation	Lys, N-terminus	Yes (HDACs)	Chromatin opening, protein stability
Methylation	Lys, Arg	Yes (demethylases)	Chromatin code, activation/repression
Proteolytic cleavage	Peptide bond	No	Activation of zymogens/proproteins
Disulfide bond	Cys	Yes (PDI/reductases)	Structural stability
Hydroxylation	Pro, Lys	No	Collagen structure
Lipidation	Gly/Cys/CAAX	Partial	Membrane anchoring

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