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IMIN 371 > MHC > Flashcards

MHC Flashcards

1
Q

What MHC does CD8 bind?

A

MHC I + peptide

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2
Q

What MHC does CD4 bind?

A

MHC II + peptide

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3
Q

Describe characteristics of MHC I

A
  • found on the surface of all nucleated cells
  • expressed in higher levels on immune cells and can be induced on cells by IFN gamma
  • they present peptides that originate from the inside of the cell (endogenous peptides)
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4
Q

Describe the structure of MHC I

A
  • comprised of 2 chains: alpha chain and beta2 microglobulin
  • peptide binding groove is formed by the alpha chain
  • peptide binding cleft consists of 2 alpha helices and a beta sheet and the ends of the cleft are closed off (limits size of peptides that can bind MHC)
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5
Q

How large are the peptides that can be bound in the binding cleft of MHC I?

A

8-10 aa long

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6
Q

What part of MHC I does CD8 interact with?

A

the alpha 3 domain

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7
Q

Describe the characteristics of MHC II

A
  • Primarily found on the surface of professional APCs (dendritic cells, macrophages, and B cells)
  • presents peptides that originate from outside of the cell (internalized Ag/ exogenous peptides)
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8
Q

Describe the structure of MHC II.

A
  • comprised of 2 chains (alpha and beta chain)
  • both chains make up the binding cleft (2 alpha helices and a beta sheet)
  • the ends of the binding cleft are open allowing for larger peptides
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9
Q

How large are the peptides that can be bound in the binding cleft of MHC II?

A

13-18 aa (they can hang off the edge of the binding cleft on both sides)

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10
Q

What part of MHC II does CD4 interact with?

A

the beta2 and alpha2 domains

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11
Q

What chromosome has the human MHC genomic reigon?

A

Chromosome 6

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12
Q

Haplotype

A

Collection of MHC genes on 1 chromosome (you get 1 haplotype from Mom and one from Dad)

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13
Q

Human leukocyte antigen (HLA) genes

A

MHC I and MHC II genes

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14
Q

What are the 3 classical MHC I genes in humans?

A

HLA-A, B and C (code for the alpha chains)
B2M is coded for on another chromosome

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15
Q

What are the 3 classical MHC II genes in humans?

A

HLA- DR,DP, and DQ (codes for the alpha and beta chains

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16
Q

Non-classical HLA-G

A

MHC I gene that protects the fetus from rejection by mom

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17
Q

Non-classical HLA-DM

A

MHC II gene related to classical MHC II genes and involved in peptide loading onto classical MHC II molecules

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18
Q

What chromosome has the murine (mouse) MHC genomic reigon?

A

chromosome 17

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19
Q

What are the 3 classical MHC I genes in mice?

A

H-2K, H-2D, and H-2L

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20
Q

What are the 3 classical MHC II genes in mice?

A

H-2A and H-2E

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21
Q

What are 3 important characteristics of classical MHC genes?

A

they are polygenic, polymorphic and their expression is co-dominant

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22
Q

polygenic

A

there are multiple genes for 1 trait

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23
Q

polymorphic

A

multiple alleles exist for 1 trait

24
Q

Where is the most variability seen in the MHC complex?

A

in the peptide binding groove

25
Q

Co-dominant expression

A

Both maternal and paternal alleles are simutaneously expressed in cells

26
Q

How many peptides can 1 MHC alleles present?

A

multiple peptides can be presented by the same MHC allele

27
Q

Anchor residues

A

amino acids at specific positions on bound peptides (different MHC class I alleles prefer different anchor residues)

28
Q

What anchor residue characteristic is important for MHC I binding?

A
  • usually hydrophobic aa
  • usually at the ends of the peptides
  • c-terminal residue is almost always an anchor residue
  • N and C termini of peptides make important contacts with MHC I
29
Q

Describe the binding of peptides to MHC I.

A

It is semi-promiscuous: the non anchor residues can vare (their aa sequence) but the anchor residues cannot (they are constant

30
Q

Where are anchor residues found in MHC II peptides?

A

Since the peptide typically extends out of MHC II the N and C terminal residues are not commonly anchor residues and the anchor residues are more often found in the aa in the middle of the peptides

31
Q

Compare and contract MHC I vs MHC II in regards to…
- peptide-binding domain
- nature of peptide-binding groove
- general size of bound peptides
- peptide motifs involved in binding to MHC molecule
- nature of bound peptides

A

MHC I:
- peptide-binding domain: alpha 1 and alpha 2
- nature of peptide-binding groove: closed at both ends
- general size of bound peptides: 8-10 aa
- peptide motifs involved in binding to MHC molecule: anchor residues at both ends of peptide and generally hydrophobic at C terminals
- nature of bound peptides: extended structure in which both ends interact with MHC groove but middle arches up and away from MHC molecule

MHC II:
- peptide-binding domain: alpha1 and beta 1
- nature of peptide-binding groove: open at both ends
- general size of bound peptides: 13-18aa
- peptide motifs involved in binding to MHC molecule: conserved residues distributed along the length of the peptide anchor
- nature of bound peptides: extended structure that is held at a constant elevation above the floo of the MHC groove (hot dog in a bun)

32
Q

How do MHC I peptides get generated?

A
  • many come from defective ribosomal products (DriPs) which are defectively folded proteins that often occur as the result of improperly spliced mRNAs or ribosomal frameshifts (includes viral proteins
33
Q

What happens to misfolded proteins?

A

They become ubiqutylated (a covalent addition of 76 aa ubiquitin molecules to lysine residues)
This requires ATP and a series of enzymes

34
Q

What happens after the misfolded proteins become ubiquitlylated?

A

They are targeted by the 26S proteasome

35
Q

Describe the structure of the 26S proteasome.

A

Consists of a 20S core and 2 19S subunits

36
Q

What does the 26S proteasome do to Ubiquilated proteins?

A
  • the 19S lid binds to the ubiquilated proteins and recycles the ubiquitin and unfolded the proteins that are not completely folded (ensures the protein enters the core)
  • the 20S core has proteases that chop up the proetins into peptides
37
Q

Immunoproteasome

A

Generated in special subunits of the 20S core of the 26S proteasome and it functions to generate a higher frequency of peptides thatare the optimal size to bind MHC I and have C terminal residues

38
Q

What proteases are encoded in the MHC reigon of the genome?

A

LMP2, LMP7, and LMP10

39
Q

What upregulates the immunoproteasome subunits?

A

IFN gamma and TNF alpha (produced in response to a viral infection)

40
Q

PA28 proteosome

A

Generated by IFN gamma secretion
This replaces the 19S subunits and allows for increased peptide generation

41
Q

TAP transporter

A
  • Transporter Associated with Ag Processing (TAP)
  • ATP dependent transporter that transfers peptides into the ER
42
Q

Describe the structure of the TAP transporter.

A

2 subunits: TAP1 and TAP2 and these are encoded for in the MHC reigon of the genome

43
Q

What types of petides does the TAP transporter transport?

A
  • 8-16 aa in size
  • often has a hydrophobic C-terminal aa
44
Q

What can happen to peptides after they are transported into the rough ER?

A

They can be further trimmed at the N-terminus to fit into MHC I by other proteases

45
Q

ERAPs

A

endoplasmic rectriculum aminopeptidases
they have little affinity for peptides less than 8 aa

46
Q

Describe the process of MHC I peptide loading.

A
  1. The class 1 alpha chain and beta2m are synthesized into the RER
  2. the parcially folded alpha chain binds the chaperone proetin Calnexin and ERp57
  3. when the beta2m binds the alpha chain the calnexin is released and replaced with other proteins
  4. the alpha chain and beta2m complex binds a second complex of proteins (peptide loading complex (PLC))
  5. The TAP transporter is linked to the alpha chain+beta2m complex by tapsin and calretulin (a chaperon protein) also binds to the complex
  6. The peptide is loaded onto the MHC I complex and dissociates from the rest of the loading complex and the MHC I +peptide travels out of the RER and to the cell surface
47
Q

WHat is the function of Calnexin and ERp57?

A

Helps fold the alpha chain but retains in parcially folded state until the beta2m binds

48
Q

Tapsin

A

Links TAP transporter to the alpha chain and beta2m complex and also facilitates peptide loading

49
Q

Bare Lymphocyte Sydrome type 1

A
  • paitents lack or have very little MHC I expression on the surface of cells
  • the number of CD8 is dramatically reduced (MHC I is critical for CD8+ cell development)
  • paitents deal with many viral infections and have problems with respiratory bacterial infections
50
Q

How are MHC II peptides preped for peptide loading?

A

The MHC II peptides are internalized via phagocytosis/ receptor mediated endocytosis/ pinocytosis. The internalized Ags are degraded by petidases in vesicles as pH of vesicles decreaases (becomes more acidic). Endocytosed Ag/peptides end up in MIIC late endosome for peptide loading

51
Q

Describe the process of how MHC II peptides are loaded.

A
  1. Class II alpha and beta chains are sythesized in the RER where is is also complexed with Ii (invarient chain)
  2. MHC II/Ii complex moves to acidic edosomal vesicle
  3. Invarient chains degraded leaving the CLIP fragment
  4. Exogenous Ag is taken up, degraded by proteases, and fuses with the MHC II/CLIP vesicles
  5. HLA-DM binds MHC II/CLIP complex and promotes the release of CLIP and it binds the internalized peptide
  6. MHC II + peptide is transported to plasma membrane for display to CD4+ T cells
52
Q

Invarient Chain (Ii)

A
  • binds all classical MHCII molecules
  • prevents ER peptides from associating with the MHC II peptide binding groove and also helps fold the MHC II molecule
  • directs MHC II out of the RER through the golgi and towards low pH endosomal compartments
53
Q

cathepsins

A

cleaves the invarient chain from the MHC II complex

54
Q

CLIP

A

class II associated invarient chain peptide
this prevents peptides from associating with the peptide binding groove

55
Q

Bare lymphocyte Syndrome type 2

A
  • cells lack MHC II expression and has reduced CD4+ T cells but CD8+ T cells are normal
  • has a SKID like phenotype
  • has a mutation in transcription factors that promote MHC II expression
56
Q

Cross Presentation

A

in some APCs exogenous Ags can get into the class I pathway

IMIN 371 (9 decks)

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